Insecticidal n-substituted (6-haloalkylpyridin-3-yl)-alkyl sulfoximines

ABSTRACT

N-Substituted (6-haloalkylpyridin-3-yl)alkyl sulfoximines are effective at controlling insects.

This application claims the benefit of U.S. Provisional Application Ser.No. 60/772,108 filed on 10 Feb. 2006 and 60/836,044 filed on 7 Aug.2006. This application also claims the benefit of U.S. patentapplication Ser. No. 11/704,842 filed on 9 Feb. 2007, now U.S. Pat. No.7,687,634. This application also claims the benefit of U.S. applicationSer. No. 12/706,513 filed on 16 Feb. 2010, now U.S. Pat. No. 8,269,016.This application also claims the benefit of U.S. application Ser. No.13/558,378 filed on 26 Jul. 2012, now allowed. The entire disclosures ofall of these applications are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

The present invention concerns novel N-substituted(6-haloalkylpyridin-3-yl)alkyl sulfoximines and their use in controllinginsects and certain other invertebrates, particularly aphids and othersucking insects. This invention also includes new synthetic proceduresfor preparing the compounds, pesticide compositions containing thecompounds, and methods of controlling insects using the compounds.

There is an acute need for new insecticides. Insects are developingresistance to the insecticides in current use. At least 400 species ofarthropods are resistant to one or more insecticides. The development ofresistance to some of the older insecticides, such as DDT, thecarbamates, and the organophosphates, is well known. But resistance haseven developed to some of the newer pyrethroid insecticides. Therefore aneed exists for new insecticides, and particularly for compounds thathave new or atypical modes of action.

U.S. Patent Application Publication 2005/0228027 A1 describes certainsulfoximine compounds including some containing(6-alkylpyridin-3-yl)alkyl groups and their use in controlling insects.It has now been discovered that (6-haloalkylpyridin-3-yl)alkylsulfoximines have greatly improved activity.

SUMMARY OF THE INVENTION

This invention concerns compounds useful for the control of insects,especially useful for the control of aphids and other sucking insects.More specifically, the invention concerns compounds of the formula (I)

wherein

X represents NO₂, CN or COOR⁴;

L represents a single bond or R¹, S and L taken together represents a4-,5- or 6-membered ring;

R¹ represents (C₁-C₄) alkyl;

R² and R³ independently represent hydrogen, methyl, ethyl, fluoro,chloro or bromo;

n is an integer from 0-3;

Y represents (C₁-C₄) haloalkyl; and

R⁴ represents (C₁-C₃) alkyl.

Preferred compounds of formula (I) include the following classes:

(1) Compounds of formula (I) wherein X is NO₂ or CN, most preferably CN.

(2) Compounds of formula (I) wherein Y is CF₃.

(3) Compounds of formula (I) wherein R² and R³ independently representhydrogen, methyl or ethyl.

(4) Compounds of formula (I) wherein R¹, S and L taken together form asaturated 5-membered ring, and n is 0, i.e., having the structure

(5) Compounds of formula (I) wherein R¹ represents CH₃ and L representsa single bond, i.e., having the structure

wherein n=1-3, most preferably n=1.

It will be appreciated by those skilled in the art that the mostpreferred compounds are generally those which are comprised ofcombinations of the above preferred classes.

The invention also provides new processes for preparing compounds offormula (I) as well as new compositions and methods of use, which willbe described in detail hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

Throughout this document, all temperatures are given in degrees Celsius,and all percentages are weight percentages unless otherwise stated.

Unless specifically limited otherwise, the term alkyl (includingderivative terms such as alkoxy), as used herein, include straightchain, branched chain, and cyclic groups. Thus, typical alkyl groups aremethyl, ethyl, 1-methylethyl, propyl, 1,1-dimethylethyl, andcyclopropyl. The term haloalkyl includes alkyl groups substituted withfrom one to the maximum possible number of halogen atoms, allcombinations of halogens included. The term halogen includes fluorine,chlorine, bromine and iodine, with fluorine being preferred.

The compounds of this invention can exist as one or more stereoisomers.The various stereoisomers include geometric isomers, diastereomers andenantiomers. Thus the compounds of the present invention include racemicmixtures, individual stereoisomers and optically active mixtures. Itwill be appreciated by those skilled in the art that one stereoisomermay be more active than the others. Individual stereoisomers andoptically active mixtures may be obtained by selective syntheticprocedures, by conventional synthetic procedures using resolved startingmaterials or by conventional resolution procedures.

The compounds of formula (Ia), wherein R¹, R², R³, R⁴, X, and Y are aspreviously defined and L is a single bond, can be prepared by themethods illustrated in Scheme A:

In step a of Scheme A, sulfide of formula (A) is oxidized withmeta-chloroperoxybenzoic acid (mCPBA) in a polar solvent below 0° C. toprovide sulfoxide of formula (B). In most cases, dichloromethane is thepreferred solvent for oxidation.

In step b of Scheme A, sulfoxide (B) is iminated with sodium azide inthe presence of concentrated sulfuric acid in an aprotic solvent underheating to provide sulfoximine of formula (C). In most cases, chloroformis the preferred solvent for this reaction.

In step c of Scheme A, the nitrogen of sulfoximine (C) can be eithercyanated with cyanogen bromide in the presence of a base, or nitratedwith nitric acid in the presence of acetic anhydride under mildlyelevated temperature, or carboxylated with alkyl (R⁴) chloroformate inthe presence of base such as 4-dimethylaminopyridine (DMAP) to provideN-substituted sulfoximine (Ia). Base is required for efficient cyanationand carboxylation and the preferred base is DMAP, whereas sulfuric acidis used as catalyst for efficient nitration reaction.

The compounds of formula (Ia), wherein X represents CN and R¹, R², R³,R⁴ and Y are as previously defined, can be prepared by the mild andefficient method illustrated in Scheme B.

In step a of Scheme B, sulfide is oxidized with iodobenzene diacetate inthe presence of cyanamide at 0° C. to give sulfilimine (D). The reactioncan be carried out in a polar aprotic solvent like CH₂Cl₂.

In step b of Scheme B, the sulfilimine (D) is oxidized with mCPBA. Abase such as potassium carbonate is employed to neutralize the acidityof mCPBA. Protic polar solvents such as ethanol and water are used toincrease the solubility of the sulfilimine starting material and thebase employed. The sulfilimine (D) can also be oxidized with aqueoussodium or potassium periodinate solution in the presence of catalystruthenium trichloride hydrate or similar catalyst. The organic solventfor this catalysis can be polar aprotic solvent such as CH₂Cl₂,chloroform, or acetonitrile.

The α-carbon of the N-substituted sulfoximine of formula (Ia), i.e.,n=1, R³=H in the (CR²R³) group adjacent to the N-substituted sulfoximinefunction can be further alkylated or halogenated (R⁵) in the presence ofa base such as potassium hexamethyldisilamide (KHMDS) to giveN-substituted sulfoximines of formula (Ib), wherein R¹, R², R³, R⁴, X, Land Y are as previously defined and Z is an appropriate leaving group,as illustrated in Scheme C. The preferred leaving groups are iodide(R⁵=alkyl), benzenesulfonimide (R⁵=F), tetrachloroethene (R⁵=Cl), andtetrafluoroethene (R⁵=Br).

Sulfoximine compounds of formula (Ic) wherein R¹, S and L taken togetherform a saturated 4-, 5- or 6-membered ring and n=1 can be prepared bythe methods illustrated in Scheme D wherein X and Y are as previouslydefined and m is 0, 1, or 2.

In step a of Scheme D, which is similar to step b of Scheme A, sulfoxideis iminated with sodium azide in the presence of concentrated sulfuricacid or with O-mesitylsulfonylhydroxylamine in a polar aprotic solventto provide sulfoximine. Chloroform or dichloromethane are the preferredsolvents.

In step b of Scheme D, similar to step c of Scheme A, the nitrogen ofsulfoximine can be either cyanated with cyanogen bromide, or nitratedwith nitric acid followed by treatment with acetic anhydride underrefluxing conditions, or carboxylated with methyl chloroformate in thepresence of base such as DMAP to provide N-substituted cyclicsulfoximine. Base is required for efficient cyanation and carboxylationand the preferred base is DMAP, whereas sulfuric acid is used ascatalyst for efficient nitration reaction.

In step c of Scheme D, the α-carbon of N-substituted sulfoximine can bealkylated with a heteroaromatic methyl halide in the presence of a basesuch as KHMDS or butyl lithium (BuLi) to give the desired N-substitutedsulfoximines. The preferred halide can be bromide, chloride or iodide.

Alternatively, the compounds of formula (Ic) can be prepared by a firstα-alkylation of sulfoxides to give α-substituted sulfoxides and then animination of the sulfoxide followed by N-substitution of the resultingsulfoximine by using the steps c, a and b respectively as describedabove for Scheme D.

The starting sulfides (A) in Scheme A can be prepared in different waysas illustrated in Schemes E, F G, H, I and J.

In Scheme E, the sulfide of formula (A₁), wherein R¹, R² and Y are aspreviously defined, n=1, and R³=H, can be prepared from the chloride offormula (E) by nucleophilic substitution with the sodium salt of analkyl thiol.

In Scheme F, the sulfide of formula (A₂), wherein R¹, R² and Y are aspreviously defined, n=3, and R³=H, can be prepared from the chloride offormula (F) by reacting with a 2-mono substituted methyl malonate in thepresence of base such as potassium tert-butoxide to provide2,2-disubstituted malonate, hydrolysis under basic conditions to form adiacid, decarboxylation of the diacid by heating to give a monoacid,reduction of the monoacid with borane-tetrahyrofuran complex to providean alcohol, tosylation of the alcohol with toluenesulfonyl chloride(tosyl chloride) in the presence of a base like pyridine to give atosylate and replacement of the tosylate with the sodium salt of thedesired thiol.

In Scheme G, the sulfide of formula (A₃), wherein R¹, R² and Y are aspreviously defined, n=2, and R³=H, can be prepared from the nitrile offormula (G) by deprotonation with a strong base and alkylation with analkyl iodide to give α-alkylated nitrile, hydrolysis of the α-alkylatednitrile in the presence of a strong acid like HCl to give an acid,reduction of the acid with borane-tetrahyrofuran complex to provide analcohol, tosylation of the alcohol with tosyl chloride in the presenceof a base like pyridine to give a tosylate and replacement of thetosylate with the sodium salt of the desired thiol.

In Scheme H, the sulfide of formula (A₄), wherein R¹, S and L takentogether represents a 4-, 5- or 6-membered ring (m=0, 1, or 2) and n is0 can be prepared from the corresponding substituted chloromethylpyridine by treatment with thiourea, hydrolysis and subsequentalkylation with the appropriate bromo chloroalkane (m=0, 1, or 2) underaqueous base conditions, and cyclization in the presence of a base likepotassium-t-butoxide in a polar aprotic solvent such as THF.

Sulfides of formula (A₁), wherein R¹, R²=CH₃, Y as previously defined,and R³=H, can be prepared alternatively via methods illustrated inScheme I. Accordingly, the appropriate enone is coupled withdimethyl-aminoacrylonitrile and cyclized with ammonium acetate in DMF toyield the corresponding 6-substituted nicotinonitrile. Treatment withmethylmagnesium bromide, reduction with sodium borohydride, chlorinationwith thionyl chloride, and nucleophilic substitution with the sodiumsalt of an alkyl thiol provide desired sulfides (A₁).

Sulfides of formula (A₁), wherein R¹=methyl or ethyl, R² and R³independently represent hydrogen, methyl or ethyl, and Y is aspreviously defined can be prepared via a variation of Scheme I, depictedin Scheme J, wherein enamines, formed from the addition of an amine,e.g., pyrrolidine, with the Michael adduct of certain sulfides withappropriately substituted α,β-unsaturated aldehydes, are coupled withsubstituted enones and cyclized with ammonium acetate in acetonitrile toyield the desired sulfides (A₁).

Sulfoximine compounds of the formula (Id) wherein n=2, R¹ and R² arehydrogen, L is a single bond, and X and Y are as previously defined canbe prepared by the method illustrated in Scheme K. Dimethylsulfide isoxidized with iodobenzene diacetate in the presence of cyanamide at 0°C. to give the corresponding sulfilimine. The reaction can be carriedout in a polar aprotic solvent like CH₂Cl₂ or THF. The sulfilimine isthen oxidized with mCPBA. A base such as potassium carbonate is employedto neutralize the acidity of mCPBA. Protic polar solvents such asethanol and water are used to increase the solubility of the sulfiliminestarting material and the base employed. The α-carbon of theN-substituted sulfoximine can be alkylated with a heteroaromatic methylhalide in the presence of a base such as KHMDS or butyl lithium (BuLi)to give the desired N-substituted sulfoximine. The preferred halide canbe bromide, chloride or iodide.

In Scheme L, sulfides of formula (A₁), wherein Y is a fluoroalkyl group,R¹ is as previously defined, and n=1 can be prepared from the6-acylpyridine or 6-formyl pyridine by reaction with diethylaminosulfurtrifluoride (DAST). Subsequent halogenation of the 3-methyl group withNBS followed by nucleophilic substitution with the sodium salt of analkyl thiol furnishes the desired sulfide.

EXAMPLES Example I Preparation of[(6-trifluoromethylpyridin-3-yl)methyl](methyl)-oxido-λ⁴-sulfanylidenecyanamide(1)

To a solution of 3-chloromethyl-6-(trifluoromethyl)pyridine (5.1 g, 26mmol) in dimethyl sulfoxide (DMSO; 20 mL) was added in one portionsodium thiomethoxide (1.8 g, 26 mmol). A violent exothermic reaction wasobserved which resulted in the reaction turning dark. The reaction wasstirred for 1 hr, then additional sodium thiomethoxide (0.91 g, 13 mmol)was added slowly. The reaction was stirred overnight, after which it waspoured into H₂O and several drops of conc. HCl were added. The mixturewas extracted with Et₂O (3×50 mL) and the organic layers combined,washed with brine, dried over MgSO₄ and concentrated. The crude productwas purified by chromatography (Prep 500, 10% acetone/hexanes) tofurnish the sulfide (A) as a pale yellow oil (3.6 g, 67%). ¹H NMR (300MHz, CDCl₃) δ 8.6 (s, 1H), 7.9 (d, 1H), 7.7 (d, 1H), 3.7 (s, 2H), 2.0(s, 3H); GC-MS: mass calcd for C₈H₈F₃NS [M]⁺ 207. Found 207.

To a solution of sulfide (A) (3.5 g, 17 mmol) and cyanamide (1.4 mg, 34mmol) in CH₂Cl₂ (30 mL) at 0° C. was added iodobenzenediacetate (11.0 g,34 mmol) all at once. The reaction was stirred for 30 min, then allowedto warm to room temperature overnight. The mixture was diluted withCH₂Cl₂ (50 mL) and washed with H₂O. The aqueous layer was extracted withethyl acetate (4×50 mL), and the combined CH₂Cl₂ and ethyl acetatelayers dried over MgSO₄ and concentrated. The crude product wastriturated with hexanes and purified by chromatography (chromatotron,60% acetone/hexanes) to furnish the sulfilimine (B) as a yellow gum(0.60 g, 14%). IR (film) 3008, 2924, 2143, 1693 cm⁻¹, ¹H NMR (300 MHz,CDCl₃) δ 8.8 (s, 1H), 8.0 (d, 1H), 7.8 (d, 1H), 4.5 (d, 1H), 4.3 (d,1H), 2.9 (s, 3H); LC-MS (ESI): mass calcd for C₉H₉F₃N₃S [M+H]⁺ 248.04.Found 248.

To a solution of m-chloroperbenzoic acid (mCPBA; 80%, 1.0 g, 4.9 mmol)in EtOH (10 mL) at 0° C. was added a solution of K₂CO₃ (1.4 g, 10 mmol)in H₂O (7 mL). The solution was stiffed for 20 min, then a solution ofsulfilimine (B) (0.60 g, 2.4 mmol) in EtOH (20 mL) was added all atonce. The reaction was stirred at 0° C. for 30 min, then allowed to warmto room temperature over the course of 1 hr. The reaction was thenquenched with aq. sodium bisulfite and the mixture was concentrated toremove ethanol. The resulting mixture was extracted with CH₂Cl₂ and thecombined organic layers dried over MgSO₄ and concentrated. The crudeproduct was purified by chromatography (chromatotron, 50%acetone/hexanes) to furnish the sulfoximine (1) as an off-white solid(0.28 g, 44%). Mp=135-137° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.8 (s, 1H),8.1 (d, 1H), 7.8 (d, 1H), 4.7 (m, 2H), 3.2 (s, 3H); LC-MS (ELSD): masscalcd for C₉H₉F₃N₃OS [M+H]⁺ 264.04. Found 263.92.

Example II Preparation of[1-(6-trifluoromethylpyridin-3-yl)ethyl](methyl)-oxido-λ⁴-sulfanylidenecyanamide(2)

To a solution of sulfoximine (1) (50 mg, 0.19 mmol) andhexamethylphosphoramide (HMPA; 17 μL, 0.10 mmol) in tetrahydrofuran(THF; 2 mL) at −78° C. was added potassium hexamethyldisilazane (KHMDS;0.5 M in toluene, 420 μL, 0.21 mmol) dropwise. The solution was stirredat −78° C. for an additional 20 min, after which iodomethane (13 μL,0.21 mmol) was added. The reaction was allowed to warm to roomtemperature over the course of 1 hr, after which it was quenched withsatd. aq. NH₄Cl and extracted with CH₂Cl₂. The organic layer was driedover Na₂SO₄, concentrated, and the crude product purified bychromatography (chromatotron, 70% acetone/CH₂Cl₂) to furnish thesulfoximine (2) as a 2:1 mixture of diastereomers (colorless oil; 31 mg,59%). ¹H NMR (300 MHz, CDCl₃) δ (major diastereomer) 8.8 (s, 1H), 8.1(d, 1H), 7.8 (d, 1H), 4.6 (q, 1H), 3.0 (s, 3H), 2.0 (d, 3H); (minordiastereomer) 8.8 (s, 1H), 8.1 (d, 1H), 7.8 (d, 1H), 4.6 (q, 1H), 3.1(s, 3H), 2.0 (d, 3H); LC-MS (ELSD): mass calcd for C₁₀H₁₀F₃N₃OS [M+H]⁺278.06. Found 278.05.

Example III Preparation of2-(6-trifluoromethylpyridin-3-yl)-1-oxidotetrahydro-1H-1λ⁴-thien-1-ylidenecyanamide(3)

To a suspension of thiourea (1.2 g, 16 mmol) in EtOH (25 mL) was added asolution of 3-chloromethyl-6-(trifluoromethyl)pyridine in EtOH (10 mL).The suspension was stirred at room temperature for 2 days, during whicha white precipitated formed. The precipitate was filtered to give thedesired amidine hyrdochloride as a white solid (2.4 g, 58%). Mp=186-188°C. No further attempt was made to purify the product. ¹H NMR (300 MHz,CDCl₃) δ 8.9 (bs, 4H), 8.4 (s, 1H), 7.6 (d, 1H), 7.3 (d, 1H), 4.2 (s,2H); LC-MS (ELSD): mass calcd for C₈H₈F₃N₃S [M+H]⁺ 236.05. Found 236.01.

To a solution of amidine hydrochloride (A) (1.8 g, 6.8 mmol) in H₂O (12mL) at 10° C. was added 10 N NaOH (0.68 mL, 6.8 mmol), which resulted inthe formation of a white precipitate. The suspension was heated at 100°C. for 30 min, then cooled back down to 10° C. Additional 10 N NaOH(0.68 mL, 6.8 mmol) was then added, followed by 1-bromo-3-chloropropane(0.67 mL, 6.8 mmol) all at once. The reaction was stirred at roomtemperature overnight, then extracted with CH₂Cl₂. The combined organiclayers were washed with brine, dried over Na₂SO₄ and concentrated tofurnish the sulfide (B) as a colorless oil (1.7 g, 96%). No furtherattempt was made to purify the product. ¹H NMR (300 MHz, CDCl₃) δ 8.6(s, 1H), 7.8 (d, 1H), 7.6 (d, 1H), 3.8 (s, 2H), 3.6 (t, 2H), 2.6 (t,2H), 2.0 (quint, 2H).

To a suspension of potassium tert-butoxide (1.5 g, 13 mmol) in THF (12mL) was added HMPA (1.7 mL, 10 mmol) followed by a solution of sulfide(B) (1.8 g, 6.7 mmol) in THF (3 mL) dropwise. The reaction was allowedto stir at room temperature overnight, followed by concentration andpurification by chromatography (Biotage, 40% EtOAc/hexanes) to furnishcyclized product (C) as an orange oil (230 mg, 15%). ¹H NMR (300 MHz,CDCl₃) δ 8.7 (s, 1H), 8.0 (d, 1H), 7.6 (d, 1H), 4.6 (dd, 1H), 3.2 (m,1H), 3.1 (m, 1H), 2.5 (m, 1H), 2.3 (m, 1H), 2.1-1.9 (m, 2H).

To a solution of sulfide (C) (230 mg, 0.99 mmol) and cyanamide (83 mg,2.0 mmol) in CH₂Cl₂ (5 mL) at 0° C. was added iodobenzenediacetate (350mg, 1.1 mmol) all at once. The reaction was stirred for 3 hr, thenconcentrated and the crude product purified by chromatography(chromatotron, 50% acetone/hexanes) to furnish the sulfilimine (D) as anorange oil (150 mg, mixture of diastereomers, 56%). ¹H NMR (300 MHz,CDCl₃) δ 8.8 (s, 1H), 7.9 (d, 1H), 7.8 (d, 1H), 4.8 (dd, 1H), 3.5 (m,2H), 2.9-2.7 (m, 2H), 2.6 (m, 1H), 2.3 (m, 1H).

To a solution of mCPBA (80%, 180 mg, 0.82 mmol) in EtOH (3 mL) at 0° C.was added a solution of K₂CO₃ (230 mg, 1.7 mmol) in H₂O (1.5 mL). Thesolution was stirred for 20 min, then a solution of sulfilimine (D) (150mg, 0.55 mmol) in EtOH (2 mL) was added all at once. The reaction wasstirred at 0° C. for 45 min, after which the solvent was decanted into aseparate flask and concentrated to give a white solid. The solid wasslurried in CHCl₃, filtered, and concentrated to furnish puresulfoximine (3) as a colorless oil (72 mg, 44%). ¹H NMR (300 MHz, CDCl₃)δ (1.5:1 mixture of diastereomers) 8.8 (s, 2H), 8.0 (d, 2H), 7.8 (d,2H), 4.7 (q, 1H), 4.6 (q, 1H), 4.0-3.4 (m, s, 4H), 3.0-2.4 (m, 8H);LC-MS (ELSD): mass calcd for C₁₁H₁₁F₃N₃OS [M+H]⁺ 290.06. Found 289.99.

Example IV Preparation of(1-{6-[chloro(difluoro)methyl]pyridin-3-yl}ethyl)(methyl)-oxido-λ⁴-sulfanylidenecyanamide(4)

(3E)-1-Chloro-4-ethoxy-1,1-difluorobut-3-en-2-one (7.36 g, 40 mmol) wasdissolved in dry toluene (40 mL) and treated with3-dimethylaminoacrylonitrile (4.61 g, 48 mmol) at room temperature. Thesolution was heated at about 100° C. for 3.5 hr. The solvent was thenremoved under reduced pressure and the remaining mixture wasre-dissolved in DMF (20 mL), treated with ammonium acetate (4.62 g, 60mmol) and stirred at room temperature overnight. Water was added to thereaction mixture and and the resulting mixture was extracted withether-CH₂CH₂ (1:2, v/v) twice. The combined organic layer was washedwith brine, dried, filtered and concentrated. The residue was purifiedon silica gel to give 3.1 g of 6-[chloro(difluoro)methyl]nicotinonitrile(A) as light colored oil in 41% yield. GC-MS: mass calcd for C₇H₃ClF₂N₂[M]⁺ 188. Found 188.

6-[Chloro(difluoro)methyl]nicotinonitrile (A) (3.0 g, 15.8 mmol) wasdissolved in anhydrous ether (25 mL) and cooled in an ice-water bath. Asolution of 3 M of methylmagnesium bromide in hexane (6.4 mL, 19 mmol)was added through a syringe. After the addition was over, the mixturewas stirred at 0° C. for 5 hr and then at room temperature for 10 hr.The reaction was quenched slowly with 1 N citric acid aqueous solutionat 0° C. and the resulting mixture was stirred at room temperature for 1hr. The pH was adjusted back to pH 7 with saturated NaHCO₃ aqueoussolution. The two phases were separated and the aqueous phase wasextracted with ethyl acetate twice. The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated. The remaining mixture was purified on silica gel elutedwith 15% acetone in hexane to give 0.88 g of the desired product1-{6-[chloro(difluoro)methyl]pyridin-3-yl}-ethanone (B) as brownish oilin 30% yield. GC-MS: mass calcd for C₈H₆ClF₂NO [M]⁺ 205. Found 205.

To a solution of 1-{6-[chloro(difluoro)methyl]pyridin-3-yl}ethanone (B)(0.85 g, 4.14 mmol) in MeOH (10 mL) at 0° C. was added NaBH₄ (0.16 g,4.14 mmol). The mixture was stirred for 30 min and 2 M HCl aqueoussolution was added until pH reached 7. Solvent was removed under reducedpressure and the remaining mixture was extracted with CH₂Cl₂ (2×50 mL).The combined organic layer was dried over anhydrous Na₂SO₄, filtered,concentrated, and dried in vacuo to give 0.798 g of analytically pure1-{6-[chloro(difluoro)methyl]-pyridin-3-yl}ethanol (C) on GC-MS as alight yellow oil in 93% yield. GC-MS: mass calcd for C₈H₆ClF₂NO [M]⁺207. Found 207.

To a solution of 1-{6-[chloro(difluoro)methyl]-pyridin-3-yl}ethanol(0.78 g, 3.77 mmol) in CH₂Cl₂ (40 mL) was added thionyl chloride (0.54mL, 7.54 mmol) dropwise at room temperature. After 1 hr, the reactionwas quenched slowly with saturated NaHCO₃ aqueous solution and the twophases were separated. The organic layer was dried over Na₂SO₄,filtered, concentrated, and dried in vacuum to give 0.83 g of the crude2-[chloro(difluoro)methyl]-5-(1-chloroethyl)pyridine (D) as brown oil in98% yield, which was directly used for the next step reaction. GC-MS:mass calcd for C₈H₇Cl₂F₂N [M]⁺ 225. Found 225.

To a solution of 2-[chloro(difluoro)methyl]-5-(1-chloroethyl)pyridine(D) (0.81 g, 3.6 mmol) in ethanol (10 mL) was added sodium thiomethoxide(0.52 g, 7.4 mmol) under stiffing in one portion at 0° C. After 10 min,the mixture was allowed to warm to room temperature and stirredovernight. The solvent ethanol was then removed under reduced pressureand the residue was re-taken into ether/CH₂Cl₂ and brine. The two phaseswere separated and the organic layer was extracted with CH₂Cl₂ one moretime. The combined organic layer was dried over anhydrous Na₂SO₄,filtered, concentrated, purified on silica gel using 5% ethyl acetate inhexane to give 0.348 g of the2-[chloro(difluoro)methyl]-5-[1-(methylthio)ethyl]pyridine (E) in 40%yield GC-MS: mass calcd for C₉H₁₀ClF₂NS [M]⁺ 237. Found 237.

To a stiffed solution of2-[chloro(difluoro)methyl]-5-[1-(methylthio)-ethyl]pyridine (E) (0.32 g,1.35 mmol) and cyanamide (0.058 g, 1.35 mmol) in THF (7 mL) was addediodobenzene diacetate (0.44 g, 1.35 mmol) in one portion at 0° C. andthe resulting mixture was stirred at this temperature for 1 hr and thenat room temperature for 2 hr. The solvent was then removed under reducedpressure and the resulting mixture was dissolved in CH₂Cl₂, washed withhalf-saturated brine, dried over anhydrous Na₂SO₄, filtered,concentrated, and purified on silica gel using 50% acetone in hexane togive 0.175 g of(1-{6-[chloro-(difluoro)methyl]pyridin-3-yl}ethyl)(methyl)-λ⁴-sulfanylidenecyanamide(F) as light-yellow oil in 48% yield. ¹H NMR (300 MHz, CDCl₃) δ 8.71 (d,J=1.8 Hz, 1H), 7.91 (dd, J=8.4, 1.8 Hz, 1H) 7.78 (d, J=8.4 Hz, 1H), 4.42(q, J=6.9 Hz, 1H), 2.64 (s, 3H), 1.92 (d, J=6.9 Hz, 3H); LC-MS: masscalcd for C₁₀H₁₀ClF₂N₃S [M+1]⁺278. Found 278.

To a stiffed solution of(1-{6-[chloro(difluoro)methyl]pyridin-3-yl}ethyl)-(methyl)-λ⁴-sulfanylidenecyanamide(F) (0.16 g, 0.6 mmol) in ethanol (10 mL) was added 20% potassiumcarbonate aqueous solution (1.24 g, 1.8 mmol) at 0° C. under stiffing.After 10 min stirring, 80% mCPBA (0.19 g, ca 0.9 mmol) was added to themixture, which was stirred at 0° C. for 2 hr after which the reactionwas quenched with a spatula of solid sodium thiosulfate. Most of thesolvent ethanol was removed under reduced pressure and an aqueoussaturated NaHCO₃-brine (1:1, v/v) solution was added and the mixtureextracted with chloroform three times. The combined organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedon silica gel using 35-50% acetone in hexane as eluent to give 0.092 gof the product(1-{6-[chloro(difluoro)-methyl]pyridin-3-yl}ethyl)(methyl)oxido-λ⁴-sulfanylidenecyanamide(4) as colorless oil in 57% yield. ¹H NMR (300 MHz, CDCl₃) δ 8.79 (s,1H), 8.09 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 4.73 (q, J=7.2 Hz,1H), 3.16 and 3.11 (2 s, 3H, a mixture of two diastereomeric α-CH₃groups between the sulfoximine and the pyridine tail), 2.00 (d, J=7.2Hz, 3H); LC-MS: mass calcd for C₁₀H₁₀ClF₂N₃OS [M-1]⁺292. Found 292.

Example V Preparation of[1-(6-trichloromethylpyridin-3-yl)ethyl](methyl)-oxido-λ⁴-sulfanylidenecyanamide(5)

A mixture of 5-ethylpyridine-2-carboxylic acid (1.98 g, 13 mmol),phenyl-phosphonic dichloride (2.8 g, 14.3 mmol), phosphoruspentachloride (7.7 g, 32 mmol) was stirred and slowly heated. Once aclear yellow liquid was formed, the mixture was heated to refluxovernight. After cooling, the volatiles were removed under reducedpressure. The residue was carefully poured into saturated sodiumcarbonate aqueous solution cooled in an ice-water bath. The aqueousphase was then extracted with CH₂Cl₂ two times. The combined organiclayer was washed with brine, dried over anhydrous Na₂SO₄, filtered,concentrated, and partially purified on silica gel eluted with 10% EtOAcin hexane to give 2.7 g of crude product containing both5-ethyl-2-(trichloromethyl)pyridine and5-(1-chloroethyl)-2-(trichloromethyl)pyridine in an approximate 3:1ratio (GC data, masses calcd for C₈H₈Cl₃N and C₈H₇Cl₄N [M]⁺ 223 and 257respectively. Found 223 and 257 respectively).

A mixture of the above-mentioned crude product (2.6 g) in carbontetrachloride (100 mL) was then treated with 80% of N-bromosuccinimide(1.9 g, 11 mmol) and benzoylperoxide (0.66 g, 0.275 mmol) and thenrefluxed overnight. The solid was filtered off, the filtrateconcentrated and the resulting residue purified on silica gel using 4%EtOAc in hexane to give 1.0 g of the desired product5-(1-bromoethyl)-2-(trichloromethyl)pyridine (A) as a yellow solid. Thecombined yield for the two steps was 25%. GC-MS: mass calcd forC₈H₇BrCl₃N [M-1-Cl]⁺ 266. Found 266.

A solution of 5-(1-bromoethyl)-2-(trichloromethyl)pyridine (A) (0.95 g,3.14 mmol) in ethanol (15 mL) was treated with sodium thiomethoxide(0.44 g, 6.29 mmol) portionwise at 0° C. The mixture was stiffed at roomtemperature overnight. The solvent ethanol was then removed under areduced pressure and the residue was re-taken into CH₂Cl₂ and brine. Thetwo phases were separated and the organic layer was dried over anhydrousNa₂SO₄, filtered, concentrated. The residue was purified on silica gelusing 5% EtOAc in hexane to give 0.57 g of the partially pure5-[1-(methylthio)ethyl]-2-(trichloromethyl)pyridine (B) in 67% crudeyield. GC-MS: mass calcd for C₉H₁₀Cl₃NS [M]⁺ 269. Found 269.

To a stirred solution of5-[1-(methylthio)ethyl]-2-(trichloromethyl)-pyridine (B) (0.55 g, 2.3mmol) and cyanamide (0.097 g, 2.3 mmol) in THF (7 mL) cooled to 0° C.was added iodobenzene diacetate (0.75 g, 2.3 mmol) in one portion. Theresulting mixture was stirred at 0° C. for 1 hr and then at roomtemperature for 2 hr. The solvent was removed in vacuo and the resultingmixture was purified on silica gel using 50% acetone in hexane to give0.254 g of (1E)-methyl{1-[6-(trichloromethyl)pyridin-3-yl]ethyl}-λ⁴-sulfanylidenecyanamide (C)as an off-white solid in 40% yield. ¹H NMR for the diastereomericmixture (300 MHz, d₆-acetone) δ 8.87 (s, 1H), 8.21-8.25 (m, 2H),4.65-4.76 (m, 1H), 2.86-2.66 (m, 3H), 1.88-1.92 (m, 3H).

To a stirred solution of(1E)-methyl{1-[6-(trichloromethyl)pyridin-3-yl]ethyl}-λ⁴-sulfanylidenecyanamide(C) (0.20 g, 0.65 mmol) in ethanol (15 mL) was added 20% aqueouspotassium carbonate solution (1.3 mL) at 0° C., followed by addition of80% mCPBA. The resulting mixture was stiffed for 2 hr at 0° C. and thenquenched with solid sodium thiosulfate. Most of the solvent wasevaporated and 1:1 aqueous saturated NaHCO₃-brine (v/v) was added andthe mixture was extracted with chloroform three times. The combinedorganic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified on silica gel using 40% acetonein hexane to give 0.10 g of[1-(6-trichloromethylpyridin-3-yl)ethyl](methyl)-oxido-λ⁴-sulfanylidene-cyanamide(5) as colorless oil in 50% yield. ¹H NMR (300 MHz, CDCl₃) δ 8.83 (s,1H), 8.12-8.23 (m, 1H), 5.15 (q, 1H), 3.37 and 3.28 (2 s, 3H, a mixtureof two diastereomeric α-CH₃ groups between the sulfoximine and thepyridine tail), 2.03 (d, 3H); LC-MS: mass calcd for C₁₀H₁₂Cl₃N₃OS [M+1]⁺328. Found 328.

Example VI Preparation of[2-(6-trifluoromethylpyridin-3-yl)ethyl](methyl)-oxido-λ⁴-sulfanylidenecyanamide(6)

To a solution of dimethylsulfide (10.0 g, 161 mmol) and cyanamide (6.7g, 161 mmol) in THF (500 mL) at 0° C. was added iodobenzenediacetate(51.8 g, 161 mmol) all at once. Let stir at 0° C. for 30 min, thenallowed reaction to warm to room temperature overnight. The reaction wasconcentrated and purified by passing through a silica gel plug, firstwith 100% hexanes, then with 100% acetone, furnishing sulfilimine (A) asa colorless oil=13.4 g (82%). ¹H NMR (300 MHz, CDCl₃) δ 2.8 (s, 6H);GC-MS: mass calcd for C₃H₆N₂S [M]⁺ , 102. Found 102.

To a solution mCPBA (80%, 25.3 g, 147 mmol) in EtOH (450 mL) at 0° C.was added solution of K₂CO₃ (40.6 g, 294 mmol) in H₂O (340 mL). After 20min, sulfilimine (10.0 g, 98 mmol) in EtOH (150 mL) was added all atonce. The suspension was stirred at 0° C. for 90 min, after which thecrude reaction mixture was concentrated to remove EtOH, then extractedwith CH₂Cl₂ (3×). The combined organic layers were washed with satd aqNaHCO₃ soln (3×), dried over Na₂SO₄ and concentrated to furnishsulfoximine (B) as a yellow solid=1.310 g (10%). ¹H NMR (300 MHz, CDCl₃)δ 3.4 (s, 6H); GC-MS: mass calcd for C₃H₆N₂OS [M]⁺ , 118. Found 118.

To a solution of sulfoximine (100 mg, 0.85 mmol) in THF (2 mL) at −78°C. was added nBuLi (2.5 M, 340 μL, 0.85 mmol) dropwise. The solution waslet solution stir for 20 min, then 5-(chloromethyl)-2-trifluoromethylpyridine (170 mg, 0.85 mmol) was added. The solution was let solutionstir at −78° C. for additional 2 h, then quenched with satd aq ammoniumchoride and extracted with CH₂Cl₂. The combined organic extracts weredried over sodium sulfate, concentrated and purified by flashchromatography (40% EtOAc/80% hexanes) to furnish[2-(6-trifluoromethylpyridin-3-yl)ethyl](methyl)-oxido-λ⁴-sulfanylidene-cyanamide(6) as a yellow solid=14.5 mg (6%); mp=83-87° C. ¹H NMR (300 MHz, CDCl₃)δ 8.69 (d, 1H), 7.85 (dd, 1H), 7.74 (d, 1H), 3.58-3.79 (m, 2H),3.38-3.46 (m, 2H), 3.30 (s, 3H); LC-MS (ELSD): mass calcd forC₁₀H₁₁F₃N₃OS [M+H]⁺ , 278. Found 278.

Example VII Preparation of[(6-difluoromethylpyridin-3-yl)methyl](methyl)-oxido-λ⁴-sulfanylidenecyanamide(7)

To a solution of 2-iodo-5-bromopyridine (18.4 g, 65 mmol) in THF (100mL) at −15° C. was added isopropylmagnesium chloride (2M, 35 mL, 70mmol) dropwise at a rate such that the temperature of the reaction didnot exceed 0° C. The reaction was stirred at −15° C. for 1 h, then DMF(7.5 mL, 97 mmol) was added dropwise at a rate such that the temperatureof the reaction did not exceed 0° C. The reaction was stirred for 30min, then warmed to room temperature for an additional 1 h. The reactionwas cooled back down to 0° C. and 2 N HCl (80 mL) was added dropwise,maintaining the temperature below 20° C. After stirring for 30 min, 2 NNaOH was added until pH 7 was reached. The organic layer was thenseparated and the aqueous layer extracted with CH₂Cl₂ (3×). The combinedorganic layers were dried over MgSO₄, concentrated and purified by flashchromatography (SiO₂, 10% EtOAc/hexanes) to furnish5-bromopyridine-2-carbaldehyde (A) as a white solid (7.3 g, 60%). ¹H NMR(300 MHz, CDCl₃) δ 10.0 (s, 1H), 8.9 (s, 1H), 8.0 (d, 1H), 7.8 (d, 1H).

To a cooled solution of 5-bromopyridine-2-carbaldehyde (A) (7.0 g, 38mmol) in CH₂Cl₂ (300 mL) at −78° C. was added diethylaminosulfurtrifluoride (DAST, 10.8 mL, 83 mmol). The reaction was allowed to warmto room temperature over the course of 6 h, then it was quenched slowlywith H₂O, washed with saturated aqueous NaHCO₃ and dried over Na₂SO₄.Concentration and purification by silica gel plug (CH₂Cl₂ eluent)furnished 5-bromo-2-difluoromethylpyridine (B) as brown crystals (5.3 g,67%). ¹H NMR (300 MHz, CDCl₃) δ 8.8 (s, 1H), 8.0 (d, 1H), 7.6 (d, 1H),6.6 (t, 1H).

To a solution of 5-bromo-2-difluoromethylpyridine (B) (1.8 g, 8.6 mmol)in THF (40 mL) at 25° C. was added isopropylmagnesium chloride (2M, 8.6mL, 17 mmol) dropwise. The reaction was allowed to stir for 2 h, thenDMF (660 μL, 8.6 mmol) was added and the reaction was stirred for anadditional 22 h. The reaction was quenched with 2M HCl and basified with1M NaOH until pH 7 reached. The organic layer was separated and theaqueous layer was extracted with CH₂Cl₂. The combined organic layerswere dried over Na₂SO₄, concentrated and purified by flashchromatography (10% EtOAc/hexanes) to furnish6-difluoromethylpyridine-3-carbaldehyde (C) as an orange oil (320 mg,24%).

To a solution of 6-difluoromethylpyridine-3-carbaldehyde (C) (500 mg,3.2 mmol) in MeOH (10 mL) at 0° C. was added NaBH₄ (60 mg, 1.6 mmol).The reaction was allowed to stir for 30 min, then 2M HCl was added untilpH 2 was reached. The resulting solution was extracted with CH₂Cl₂ (3×)and the combined organic layers dried over Na₂SO₄ and concentrated tofurnish (6-difluoromethylpyridin-3-yl)methanol (D) as an orange oil (420mg, 82%) which was used in the next step without further purification.¹H NMR (300 MHz, CDCl₃) δ 8.6 (s, 1H), 7.9 (d, 1H), 7.6 (d, 1H), 6.6 (t,1H), 4.8 (s, 2H).

To a solution of (6-difluoromethylpyridin-3-yl)methanol (D) (450 mg, 2.8mmol) in CH₂Cl₂ (10 mL) at room temperature was SOCl₂ (230 μL, 3.1mmol). The reaction was allowed to stir for 1 h, then the reaction wasquenched slowly with saturated aqueous NaHCO₃. The aqueous phase wasextracted with CH₂Cl₂ (3×) and the combined organic layers were driedover Na₂SO₄ and concentrated to furnish the resulting solution wasextracted with CH₂Cl₂ (3×) and the combined organic layers dried overNa₂SO₄ and concentrated to furnish5-chloromethyl-2-difluoromethylpyridine (E) as a reddish brown oil (490mg, 98%) which was used in the next step without further purification.¹H NMR (300 MHz, CDCl₃) δ 8.7 (s, 1H), 7.9 (d, 1H), 7.6 (d, 1H), 6.6 (t,1H), 4.6 (s, 2H).

To a solution of sodium thiomethoxide (240 mg, 3.3 mmol) in EtOH (10 ml)at room temperature was added a solution of5-chloromethyl-2-difluoromethylpyridine (E) (490 mg, 2.8 mmol) in EtOH(3 mL). The reaction was allowed to stir for 9 h, then the reaction wasconcentrated, taken up in Et₂O, and washed with H₂O. The organic phasewas dried over Na₂SO₄ and concentrated to furnish2-difluoromethyl-5-methylthiomethyl-pyridine (F) as an orange oil (422mg, 81%) which was used in the next step without further purification.¹H NMR (300 MHz, CDCl₃) δ 8.6 (s, 1H), 7.8 (d, 1H), 7.6 (d, 1H), 6.6 (t,1H), 3.7 (s, 2H), 2.0 (s, 3H).

[(6-Difluoromethylpyridin-3-yl)methyl](methyl)-oxido-λ⁴-sulfanylidenecyanamide(7) was synthesized from 2-difluoromethyl-5-methylthiomethylpyridine (F)in two steps as described in Examples I-B and I-C. Isolated as a whitesolid (51% yield). ¹H NMR (300 MHz, CDCl₃) δ 8.7 (s, 1H), 8.0 (d, 1H),7.8 (d, 1H), 6.7 (t, 1H), 4.7 (dd, 2H), 3.2 (s, 3H); LC-MS (ELSD): masscalcd for C₉H₁₀F₂N₃OS [M+H]⁺ , 246. Found 246.

Example VIII Preparation of[1-(6-difluoromethylpyridin-3-yl)ethyl](methyl)-oxido-λ⁴-sulfanylidenecyanamide(8)

[1-(6-difluoromethylpyridin-3-yl)ethyl](methyl)-oxido-λ⁴-sulfanylidenecyanamide(8) was synthesized from[(6-difluoromethylpyridin-3-yl)methyl](methyl)-oxido-λ⁴-sulfanylidenecyanamide(7) in one step as described in Example II. Isolated as a colorless oil(74% yield) and a 1:1 mixture of diastereomers. ¹H NMR (300 MHz, CDCl₃)δ (mixture of two diastereomers) 8.7 (s, 2H), 8.0 (d, 2H), 7.8 (d, 2H),6.7 (t, 2H), 4.6 (q, 2H), 3.1 (s, 3H), 3.0 (s, 3H), 2.0 (d, 6H); LC-MS(ELSD): mass calcd for C₁₀H₁₂F₂N₃OS [M+H]⁺ , 260. Found 260.

Example IX Preparation of[1-(6-pentafluoroethylpyridin-3-yl)ethyl](methyl)-oxido-λ⁴-sulfanylidenecyanamide(9)

(E)-1-Ethoxy-4,4,5,5,5-pentafluoropent-1-en-3-one (1.09 g, 5 mmol) inanhydrous ethyl ether (5 mL) was treated with1-((E)-3-methylthiobut-1-enyl)pyrrolidine (0.85 g, 5 mmol) in 2 mL dryether at −15° C. over a period of 5 min and the reaction was continuedfor 20 min. Then the temperature was allowed to rise to room temperatureand the reaction continued for 3 h. The solvent was removed underreduced pressure and the residue re-dissolved in anhydrous DMF (5 mL).Ammonium acetate (0.58 g, 7.5 mmol) was added and the mixture stirred atroom temperature over a weekend. Water was added and mixture extractedwith ether three times. The combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄, filtered, concentrated, and purifiedon silica gel eluted with 8% EtOAc in hexane (v/v) to give 0.16 g of thedesired 5-(1-methylthioethyl)-2-pentafluoroethylpyridine (A) as brownishcolored oil in 12% yield. GC-MS: mass calcd for C₁₀H₁₁F₂N₃S [M]⁺ 271.Found 271.

To a stiffed solution of the5-(1-methylthioethyl)-2-pentafluoro-ethylpyridine (A) (0.16 g, 0.6 mmol)and cyanamide (0.025 g, 0.6 mmol) in THF (3 mL) cooled to 0° C. wasadded iodobenzene diacetate (0.19 g, 0.6 mmol) in one portion and theresulting mixture was stiffed at 0° C. for 2 h and then at roomtemperature overnight. The solvent was removed in vacuo and theresulting mixture was suspended in brine-saturated NaHCO₃ (9:1), whichwas then extracted with CH₂Cl₂-EtOAc (1:1, v/v) two times. The combinedorganic layer was dried over Na₂SO₄, filtered, concentrated, and driedto give 0.16 g of(1-{6-[pentafluoroethyl]pyridin-3-yl}ethyl)(methyl)-λ⁴-sulfanylidenecyanamide(B) as a brownish oil in 85% yield. LC-MS: mass calcd for C₁₁H₁₀F₅N₃S[M]⁺ 311.28. Found [M-1]⁺309.84

To a stiffed solution of the 80% 3-chloroperoxybenzoic acid (0.17 g, ca0.8 mmol) in ethanol (3 mL) cooled to 0° C. was added 20% aqueouspotassium carbonate (1.0 mL, 1.5 mmol and the resulting mixture wasstiffed at 0° C. for 20 min. Then(1-{6-[pentafluoroethyl]pyridin-3-yl}ethyl)(methyl)-λ⁴-sulfanylidenecyanamide(B) was added at once and the mixture was stirred at 0° C. for 1 h. Thereaction was quenched with a small spatula of solid sodium thiosulfate.Most of the solvent was evaporated and brine solution was added and themixture extracted with CH₂Cl₂ three times. The combined organic layerwas dried over Na₂SO₄, filtered and concentrated and the residue waspurified on silica gel using 10% acetone in CH₂Cl₂ (v/v) to give 0.089 gof[1-(6-pentafluoroethylpyridin-3-yl)ethyl](methyl)-oxido-λ⁴-sulfanylidenecyanamide(9) as a white solid in 54% yield. LC-MS: mass calcd for C₁₀H₁₀F₅N₃OS[M]⁺ 327.28. Found [M-1]⁺325.83.

Example X Preparation of2-[(6-trifluoromethylpyridin-3-yl)methyl]-1-oxidotetrahydro-1H-1λ⁴-thien-1-ylidenecyanamide(10)

1-Oxidotetrahydro-1H-1λ⁴-thien-1-ylidenecyanamide (A) was prepared fromtetrahydrothiophene by a two step procedure as described in ExamplesVI-A and VI-B (69% yield). ¹H NMR (300 MHz, CDCl₃) δ 3.5 (m, 2H), 3.3(m, 2H), 2.3-2.5 (m, 4H); GC-MS: mass calcd for C₅H₈N₂OS [M+H]⁺ , 144.Found 144.

To a solution of 1-oxidotetrahydro-1H-1λ⁴-thien-1-ylidenecyanamide (A)(200 mg, 1.4 mmol) in THF (10 ml) at −78° C. was added LDA solution inTHF (1.8M, 850 μL, 1.5 mmol). The reaction was allowed to stir for 45min, then 5-chloromethyl-2-trifluoromethylpyridine (300 mg, 1.5 mmol)was added dropwise. The solution was allowed to stir at −78° C. for 1 h,then it was warmed to 0° C. for an additional 2 h. The reaction was thenquenched with saturated aqueous NH₄Cl and extracted with CH₂Cl₂. Thecombined organic layers were dried over Na₂SO₄, concentrated, andpurified by flash chromatography to furnish2-[(6-trifluoromethylpyridin-3-yl)methyl]-1-oxidotetrahydro-1H-1λ⁴-thien-1-ylidenecyanamide(10) as a yellow oil (41 mg, 9%). IR (film) 2946, 2194, 1339 cm⁻¹, ¹HNMR (300 MHz, CDCl₃) δ (mixture of two diastereomers) 8.6 (s, 2H), 7.8(m, 2H), 7.7 (d, 1H), 7.6 (d, 1H), 3.4-3.8 (m, 7H), 3.3 (m, 1H), 3.0-3.2(m, 2H), 1.9-2.6 (m, 8H); LC-MS (ELSD): mass calcd for C₁₂H₁₃F₃N₃OS[M+H]⁺ , 304. Found 304.

Example XI Preparation of2-trifluoromethyl-5-(1-{methyl(oxido)[oxido(oxo)hydrazono]-λ⁴-sulfanyl}ethyl)pyridine(11)

To a solution of 5-(1-methylthioethyl)-2-trifluoromethylpyridine (2.0 g,9 mmol) in CHCl₃ (20 mL) at 0° C. was added solution of mCPBA (2.1 g, 10mmol) in CHCl₃ (25 mL) over the course of 1.5 h. The solution wasstirred an additional 2 h, then it was concentrated and purified byflash chromatography (10% MeOH/CH₂Cl₂) to furnish5-(1-methylsulfinylethyl)-2-trifluoromethylpyridine (A) as a yellow oil(710 mg, 33%) and a ˜2:1 mixture of diastereomers. ¹H NMR (300 MHz,CDCl₃) δ (major diastereomer) 8.7 (s, 1H), 7.8 (d, 1H), 7.7 (d, 1H), 4.0(q, 1H), 2.4 (s, 3H), 1.75 (d, 3H); (minor diastereomer) 8.6 (s, 1H),7.9 (d, 1H), 7.7 (d, 1H), 3.8 (q, 1H), 2.3 (s, 3H), 1.8 (d, 3H); LC-MS(ELSD): mass calcd for C₉H₁₁F₃NOS [M+H]⁺ , 238. Found 238.

To a solution of 5-(1-methylsulfinylethyl)-2-trifluoromethylpyridine (A)(600 mg, 2.5 mmol) in CHCl₃ (5 mL) at 0° C. was added sodium azide (260mg, 4.0 mmol) and H₂SO₄ (1 mL). The reaction was warmed to 55° C. untilgas evolution was observed, then it was cooled back down to roomtemperature overnight. The liquid was decanted into a separate flask andthe residual syrup was dissolved in H₂O, basified with Na₂CO₃ andextracted with CH₂Cl₂. The combined organic layers were dried overNa₂SO₄, concentrated and purified by flash chromatography to furnish5-[1-(methylsulfonimidoyl)ethyl]-2-trifluoromethylpyridine (B) as ayellow oil (130 mg, 20%) and a ˜1:1 mixture of diastereomers. ¹H NMR(300 MHz, CDCl₃) δ (mixture of diastereomer) 8.8 (d, 2H), 8.0 (dd, 2H),7.8 (d, 2H), 4.4 (m, 2H), 2.9 (s, 3H), 2.85 (s, 3H), 1.8 (m, 6H); LC-MS(ELSD): mass calcd for C₉H₁₁F₃N₂OS [M]⁺ , 252. Found 252.

To a solution of5-[1-(methylsulfonimidoyl)ethyl]-2-trifluoromethylpyridine (B) (100 mg,0.4 mmol) in CH₂Cl₂ (2 mL) at 0° C. was added HNO₃ (16 μL, 0.4 mmol)dropwise. To the resulting suspension was added acetic anhydride (750μL) and concentrated H₂SO₄ (5 μL) and the mixture was heated to 40° C.The suspension slowly became homogeneous over the course of 15 min. Thesolvent was then removed and the crude residue was dissolved in H₂O.Solid Na₂CO₃ was added until pH 8 was reached and the aqueous phase wasextracted with CH₂Cl₂. The combined organic layers were dried overNa₂SO₄, concentrated and purified by flash chromatography to furnish2-trifluoromethyl-5-(1-{methyl(oxido)-[oxido(oxo)hydrazono]-λ⁴-sulfanyl}ethyl)pyridine(11) as a yellow oil (22 mg, 19%) and a 1:1 mixture of diastereomers. ¹HNMR (300 MHz, CDCl₃) δ (mixture of diastereomers) 8.8 (d, 2H), 8.1 (m,2H), 7.8 (m, 2H), 5.1 (q, 1H), 5.0 (q, 1H), 3.3 (s, 3H), 3.25 (s, 3H),2.0 (m, 6H); LC-MS (ELSD): mass calcd for C₉H₁₁F₃N₃O₃S [M+H]⁺ , 298.Found 298.

Example XII Preparation of[6-(1,1-difluoroethyl)pyridin-3-yl)ethyl](methyl)-oxido-λ4-sulfanylidenecyanamide(12)

To a solution 5-methyl-2-acetylpyridine (9.9 g, 73.3 mmol) in moleculesieves-dried CH₂Cl₂ (150 mL) was added diethylamino sulfolnyltrifluoride(DAST) (25.8 g, 260 mmol) at room temperature and the mixture wasstiffed at room temperature overnight. More DAST (12 g, 74 mmol) wasadded and the reaction continued for two more days after which anadditional DAST (3.8 g, 23 mmol) was added and the reaction continuedfor another 3 days. After the reaction was quenched slowly withsaturated NaHCO₃ at 0° C., the organic phase was separated, dried overNa₂SO₄, filtered, and concentrated. The residue was purified on silicagel eluted with 8% EtOAc in hexane to give 3.91 g of2-(1,1-difluoroethyl)-5-methylpyridine (A) as a light brownish oil in34% yield. GC-MS: mass calcd for C₈H₉F₂N [M]⁺ 157. Found 157.

A mixture of 2-(1,1-difluoroethyl)-5-methylpyridine (A) (2.0 g, 12.7mmol), N-bromosuccinimide (2.2 g, 12.7 mmol) and benzoylperoxide (0.15g, 0.63 mmol) in carbon tetrachloride (100 mL) was refluxed overnight.After the solid was removed by filtration, the filtrate wasconcentrated. The residue was re-dissolved in ethanol (40 mL) and sodiumthiomethoxide (1.33 g, 19 mmol) was added at room temperature andstirred for 3 h. The solvent was removed under reduced pressure and theremaining mixture was dissolved in CH₂Cl₂ and water. After separation,the organic layer was dried over Na₂SO₄, filtered and concentrated. Thecrude product 2-(1,1-difluoroethyl)-5-methylthiomethyl-pyridine (B) was94% pure on GC/MS, which was used directly for the next reaction withoutfurther purification. GC-MS: mass calcd for C₉H₁₁F₂NS [M]⁺ 203. Found203.

To a stirred solution of2-(1,1-difluoroethyl)-5-methylthiomethylpyridine (B) (1.22 g. 6.0 mmol)and cyanamide (0.25 g, 6.0 mmol) in THF (7 mL) cooled to 0° C. was addediodobenzene diacetate (1.93 g, 6.0 mmol) in one portion and theresulting mixture was stirred at 0° C. for 1 h and then at roomtemperature for 2 h. The solvent was removed in vacuo and the resultingmixture was purified on silica gel using 60% acetone in hexane (v/v) togive 1.22 g of[(6-(1,1-difluoroethylpyridin-3-yl)methyl](methyl)-λ⁴-sulfanylidenecyanamide(C) (84% yield) as brownish oil which turned into a brownish solid afterstanding in the refrigerator overnight. LC-MS: mass calcd forC₁₀H₁₁F₂N₃S [M]⁺ 243.28. Found [M+1]⁺ 244.11.

To a 100 ml round bottom flask equipped with magnetic stiffer, additionfunnel, and thermometer was charged the sodium periodate (0.95 g, 4.44mmol) and water (12 mL). After the solid had dissolved, 15 mL of CH₂Cl₂was added followed by the ruthenium trichloride hydrate (0.033 g, 0.15mmol).[(6-(1,1-difluoroethylpyridin-3-yl)methyl](methyl)-λ⁴-sulfanylidenecyanamide(C) (0.72 g, 2.96 mmol) dissolved in 5 mL of CH₂Cl₂ was added dropwiseover a period of 30 min. The mixture was stirred rapidly at roomtemperature for 1.5 h and then filtered through a filtering paper toremove some insolubles. The mixture was then separated in separationfunnel after ethyl acetate was added to facilitate the separation. Theaqueous phase was extracted with CH₂Cl₂ twice. The combined organics waswashed with brine, dried over dry Na₂SO₄, filtered, concentrated, andbriefly purified on silica gel with 70% acetone in hexane to give 0.652g of the desired product[(6-(1,1-difluoroethylpyridin-3-yl)methyl](methyl)-oxidoλ⁴-sulfanylidenecyanamide (D) as a white solid in 87% yield. LC-MS: masscalcd for C₁₀H₁₁F₂N₃OS [M]⁺ 259.28. Found [M+1]⁺ 260.02.

To a solution of[(6-(1,1-difluoroethylpyridin-3-yl)methyl](methyl)-oxidoλ⁴-sulfanylidenecyanamide (D) (0.55 g, 2.0 mmol) and HMPA (0.09 mL, 0.55mmol) in 20 mL anhydrous THF was added 0.5 M potassiumbis(trimethylsilyl)amide in toluene (4.4 mL, 2.2 mmol) at −78° C.dropwise. After 45 min, iodomethane (0.14 mL, 2.2 mmol) was added in oneportion via a syringe. Ten minutes later, the temperature was allowed torise to 0° C. and mixture continued to stir for 1.5 h. The reaction wasquenched with saturated aqueous NH₄Cl, diluted with brine, extractedonce each with EtOAc and CH₂Cl₂. The combined organic layer was driedover Na₂SO₄, filtered, and concentrated. The residue was purified bypreparative HPLC to give 0.15 g of the desired[6-(1,1-difluoroethyl)pyridin-3-yl)ethyl](methyl)-oxido-)⁴-sulfanylidenecyanamide(12) in 26% yield. LC-MS: mass calcd for C₁₁H₁₃F₂N₃OS [M]⁺ 273.31. Found[M+1]⁺ 274.21.

Examples XIII-XXI Insecticidal Testings

The compounds identified in the foregoing examples were tested againstcotton aphid, green peach aphid, sweet potato whitefly, brownplanthopper, green leafhopper, termite, cat flea and/or brown dog tickusing procedures described hereinafter.

Example XIII Insecticidal Test for Cotton Aphid (Aphis gossvpii) inFoliar Spray Assay

Squash with fully expanded cotyledon leaves were trimmed to onecotyledon per plant and infested with cotton aphid (wingless adult andnymph) 1 day prior to chemical application. Each plant was examinedbefore chemical application to ensure proper infestation (ca. 30-70aphids per plant). Compounds (2 mg) were dissolved in 2 ml ofacetone:methanol (1:1) solvent, forming stock solutions of 1000 ppm. Thestock solutions were then diluted with a diluent consisting 80 parts of0.025% Tween 20 in H₂O and 20 parts of acetone: methanol (1:1). Ahand-held Devilbiss sprayer was used to apply the test solutions untilrunoff to both sides of the squash cotyledon leaves. Four plants (4replications) were used for each concentration of each compound.Reference plants (solvent check) were sprayed with the diluent only.Treated plants were held in a holding room for 3 days at approximately23° C. and 40% RH before the number of live aphids on each plant wasrecorded. Insecticidal activity was measured by Corrected % Controlusing Abbott's correction formula and presented in Table 1:

Corrected % Control=100*(X−Y)/X

-   -   where X=No. of live aphids on solvent check plants        -   Y=No. of live aphids on treated plants

TABLE 1 % Control of cotton aphid on squash (foliar spray) Cmpd # 0.049ppm 0.195 ppm 0.781 ppm 3.13 ppm 1 A A A A 2 A A A A 3 A A A A 4 A A A A5 E B A A 6 H H B B 7 F B A A 8 C A A A 9 H H E A 10 H H D C 11 D D A A12 H H A AIn each case of Table 1 the rating scale is as follows:

% Control (or Mortality) Rating 90-100 A 80-89 B 70-79 C 60-69 D 50-59 ELess than 50 F Inactive G Not tested H

The compounds that showed high activities against cotton aphid in Table1 were selected for further testing against green peach aphid usingprocedures described hereinafter.

Example XIV Insecticidal Test for Green Peach Aphid (Myzus persicae) inFoliar Spray Assay

Cabbage seedlings grown in 3-inch pots, with 2-3 small (3-5 cm) trueleaves, were used as test substrate. The seedlings were infested with20-50 green peach aphids (wingless adult and nymph) 2-3 days prior tochemical application. Four seedlings were used for each treatment.Compounds (2 mg) were dissolved in 2 ml of acetone:methanol (1:1)solvent, forming stock solutions of 1000 ppm. The stock solutions werethen diluted with a diluent consisting 80 parts of 0.025% Tween 20 inH₂O and 20 parts of acetone:methanol (1:1). A hand-held Devilbisssprayer was used for spraying the test solutions to both sides ofcabbage leaves until runoff Reference plants (solvent check) weresprayed with the diluent only. Treated plants were held in a holdingroom for three days at approximately 23° C. and 40% RH prior to grading.Evaluation was conducted by counting the number of live aphids per plantunder a microscope. Insecticidal activity was measured by using Abbott'scorrection formula:

Corrected % Control=100*(X−Y)/X

-   -   where X=No. of live aphids on solvent check plants        -   Y=No. of live aphids on treated plants            The Corrected % Control values from assays are given in            Table 2.

TABLE 2 Activity against green peach aphid on cabbage % Control at ppm,foliar spray Cmpd # 0.195 ppm 0.781 ppm 3.125 ppm 1 G F A 2 B A A 3 F FD 4 B A A 5 G F B 8 F F F 11 C B A 12 H E B

In each case of Table 2 the rating scale is the same as that used forTable 1.

The compounds that showed high activities against green peach aphid inTable 2 were selected for further testing against brown planthopper andgreen leafhopper using procedures described hereinafter.

Example XV Insecticidal Test for Brown Planthopper (Nilaparvata lugens)and Green Leafhopper (Nephotettix sp.)

A foliar spray assay and a root-uptake systemic assay were performed onboth brown planthopper and green leafhopper. Four-week-old riceseedlings were submerged in 3-cm depth of water in the bottom portion(high 5 cm, diameter 3 cm) of a 2-part glass cylinder (high 18 cm,diameter 3 cm). A metal screen was used to hold the seedlings within thebottom portion. Scotch tape was used to bind the two portions of thecylinder after setting up the seedlings. A metal cap was used to coverthe cylinder. There were 4 cylinders for each treatment. The testcompound was dissolved in acetone to make a 10,000 ppm stock solution.For the foliar spray assay, this stock solution was diluted with waterto make 10, 2.5, 0.31, 0.08 and 0.02 ppm test solutions. A volume of 0.5ml of a test solution or solvent blank as check was sprayed into theglass cylinder. For systemic test, the stock solution was incorporatedat final test concentrations of 10, 2.5, 0.31, 0.08 and 0.02 ppm in thewater in which rice seedlings were submerged. In both foliar spray andsystemic tests, five laboratory-reared 3^(rd) instar nymphs of brownplanthopper or green leafhopper were introduced into each cylinder 3 hrafter insecticide application. The treated test units were kept in agrowth chamber with conditions set as followings: Temperature 28±0.5°C.; Relative humidity 70±0.5%; Photoperiod 14 hr light: 8 hr dark.Mortality of hoppers was observed at 2 and 6 days after infestation. Thecorrected % Control values relative to mortality in the solventreference are given in Tables 3 and 4.

TABLE 3 Foliar spray activity against brown planthopper and greenleafhopper on rice. % Control at ppm against % Control at ppm againstgreen leafhopper brown planthopper Comp # 0.02 0.08 0.31 2.5 10 0.020.08 0.31 2.5 10 2 D A A A A F E A A A 4 E B A A A F E B A A

TABLE 4 Systemic activity against brown planthopper and green leafhopperon rice. % Control at ppm against % Control at ppm green leafhopperagainst brown planthopper Comp # 0.02 0.08 0.31 2.5 10 0.02 0.08 0.312.5 10 2 D B A A A F C A A A 4 E C A A A F E A A AIn each case of Tables 3 and 4 the rating scale is the same as that usedfor Table 1.

Compound 2 was selected for advanced testing against sweet potatowhitefly, green peach aphid, termite, cat flea and brown dog tick usingprocedures described hereinafter.

Example XVI Insecticidal Test for Sweet Potato Whitefly (Bemisia tabaci)in Foliar Spray Assay

This test was designed to measure the capability of whitefly eggs and/oryoung nymphs to develop to large nymphs. Cotton seedlings at the growthstage of one or two expanding true leaf were trimmed so that only thefirst true leaf remained (cotyledon leaves were also removed). Theplants were pre-infested with sweet potato whitefly eggs by keepingplants next to the colony-keeping plants for two days. The infestedplants were carefully checked for presence of similar egg density beforeuse in the insecticidal tests. Master solutions of test compounds at1000 ppm were prepared in acetone:methanol (1:1). The 12.5 ppm spraysolutions were then made by diluting 0.188 mL of the master solutionwith 14.812 ml of 0.025% Tween 20 in water. The lower concentrationswere made by diluting the 12.5 ppm spray solution with a diluentconsisting 98.75 parts of 0.025% Tween 20 in water and 1.25 parts ofacetone:methanol (1:1). The diluent was used as solvent control. Thetest solutions were sprayed with a hand-held Devilbiss sprayer untilrunoff to both sides of the infested cotton leaves. Four plants (4replications) were used for each treatment. Treated plants were held ina holding room for 12 days at approximately 23° C. and 40% RH beforeevaluation. To evaluate the efficacy of the compounds, the number oflive large nymphs in an area of 1 square inch on the lower surface ofthe treated cotton leaves was counted under a microscope. Insecticidalactivity was determined by Corrected % Control using Abbott's correctionformula and presented in Table 5:

Corrected % Control=100*(X−Y)/X

-   -   where X=No. of live large nymphs on solvent check plants        -   Y=No. of live large nymphs on treated plants

TABLE 5 Activity against sweet potato whitefly on cotton % Control atppm, foliar spray Comp # 0.781 ppm 3.125 ppm 12.500 ppm 2 80 94 100

Example XVII Insecticidal Test for Green Peach Aphid (Myzus persicae) inRoot Uptake Assay

Systemic activity of compound 2 against green peach aphid was evaluatedin a root uptake assay. Bell peppers (Capsicum annum var. CaliforniaWonder) was used as test plant seeded and grown in rock wool plugs.Plants were grown to expanding 1^(st) true leaf stage. The rock woolplugs containing individual plants were placed in 1-ounce cups andsurrounded with white clean sand. Five plants were used for eachtreatment. Stock solution of 1000 ppm was made by dissolving 2 mg oftechnical test compound in 2 mL acetone. The highest test concentration(10 ppm, 0.05 mg/5 ml) was prepared by diluting 0.32 mL stock solutionwith 1.6 mL acetone and 30.08 mL DI water, containing 6% acetone. Lowertest concentrations were prepared by sequentially diluting 6.5 mL higherconcentration (start from the 10 ppm test solution) with 26.0 mlacetone:DI water (6:94). A volume of 5 mL was applied to each cup (eachplant). Use 6% acetone in water as solvent check. After insecticideapplication, the seedlings were infested with green peach aphids andheld in a growth chamber (25° C., 50% R.H, 16 hr light: 8 hr dark).Number of live aphid on each plant was counted at 3 days afterinfestation. Calculations for % control were based on a corrected basiscompared to the populations on the solvent check plants.

Corrected % Control=100*(X−Y)/X

-   -   where X=No. of live aphids on solvent check plants        -   Y=No. of live aphids on treated plants            The Corrected % Control values from lower test rates are            given in Table 6.

TABLE 6 Systemic activity against green peach aphid on pepper % Control,root uptake systemic Comp # 0.08 ug/plant 0.4 ug/plant 2 ug/plant 10ug/plant 2 61 95 100 100

Example XVIII Insecticidal Test for Cotton Aphid (Aphis gossvpii) inSeed Coating ASSAY

Compound 2 was tested in an assay designed to evaluate its systemicactivity for control of cotton aphid through seed-coating prior toplanting. The crop used in this assay was a hybrid squash (var.Pic-N-Pic). Test compound was formulated in a 10% SC formulation. Forthe 1 mg/seed treatment, the original 10% formulation was used. For the0.1 mg/seed treatment, the 10% formulation were diluted 10× with DIwater before application. Ten squash seeds were used for each treatment.Seeds were placed on waxed paper and a pipette was used to apply theoriginal or diluted formulations to each seed. One half (5 ul) of thesample was spread onto one side of a seed. Once dried (approximately 1hr), the seed was flipped over and the 2nd half of sample was spreadover the other side. The air-dried, treated seeds were individuallyplanted into 3 inch pots containing metro mix. The pots were placed on aCalifornia cart and moved into the greenhouse for sub watering only.Thirteen days later, when the seedlings were approximately 9 inch tallwith three expanding true leaves, the 1st leaf was infested withapproximately 40 wingless aphids. The infested plants were kept in anenvironmental holding room (23C, 40% RH, 16 hr light: 8 hr dark) forthree days before the number of live aphids was counted under amicroscope. Calculations for % control were based on a corrected basiscompared to the populations on the reference plants germinated fromseeds treated with the formulation blank.

Corrected % Control=100*(X−Y)/X

-   -   where X=No. of live aphids on reference plants        -   Y=No. of live aphids on treated plants            The Corrected % Control values from assays are given in            Table 7.

TABLE 7 Systemic activity against cotton aphid on squash % Control, rootuptake systemic Comp # 0.1 mg/seed 1 mg/seed 2 99.7 100

Example XIX Insecticidal Test for Eastern Subterranean Termite(Reticulitermes flavipes) in Filter Paper Assay

Activity of Compound 2 was evaluated for its activity on Easternsubterranean termite. Technical material of the test compound wasformulated in acetone on a wt/wt basis to deliver 1000, 500, 200, 50,12.5, 3.12 and 0.78 ppm to 42.5 mm Whatman No. 1 filter papers per 200ul of pipetted solution. Each test concentration was applied to sixfilter papers (6 reps). Six acetone-only control units and six DIwater-only control units were also prepared. The filter papers weredried overnight in the fume hood before they were placed into 60×15 mmFisher Brand plastic Petri dishes. A volume of 200 ul DI water waspipetted onto each filter paper at the time of test set-up, just priorto infesting with termites. Ten worker termites were added to each Petridish and covered. The infested Petri dishes were put in the laboratoryConviron at 28° C. and 60% RH. Termite mortality was recorded at 1, 2,4, 7, and 10 days after infestation (DAI). Throughout the duration ofthe test, an average of 150 ul of DI water was added daily to the filterpapers to retain moisture. Results are presented in Table 8.

TABLE 8 Activity against Eastern subterranean_termite. % Termitemortality Comp # Conc. 1 DAI 2 DAI 4 DAI 7 DAI 10 DAI 2 0.78 ppm 7 17 5873 80 3.13 ppm 25 48 67 83 87 12.5 ppm 48 67 90 100 100 50 ppm 55 72 98100 100 200 ppm 55 72 80 100 100 500 ppm 63 82 98 100 100 1000 ppm 87 90100 100 100 Acetone — 0 0 0 2 3 Control DI Water — 7 7 7 7 7 Control

Example XX Insecticidal Test for Cat Flea (Ctenocephalides felis) inFilter Wool Assay

Compound 2 was evaluated in a dose response series to establish therange of activity of the test compound. Technical material was dissolvedin acetone and diluted with the same solvent to obtain the testconcentrations. Bioassays were conducted by treating polyester aquariumfilter wool with 1.0 ml of the test solution, thoroughly saturating thesubstrate and allowing it to dry for at least 1 hour. The dry filterwool was then placed into 10 cm plastic Petri dishes and covered withthe lid. Each treatment was replicated 5 times. Approximately 15 unfedcat flea adults were placed into each replicate of each dosage beingevaluated. Mortality was assessed at 2, 8, 24 and 48 hours afterintroduction of the fleas into the test system. The mean percentmortality for each dosage group and time interval was determined andresults from the 48-hour observation are presented in Table 9.

TABLE 9 Activity against cat flea. Comp # Conc. % Flea mortality 2 5 ppm18 50 ppm 25 500 ppm 40 5,000 ppm 57

Example XXI Insecticidal Test for Brown Dog Tick (Rhipicephalussanguineus) in Glass Plate Assay

Compound 2 was evaluated in a dose response series to establish therange of activity of the test compound. Technical material was dissolvedin acetone and diluted with the same solvent to obtain the testconcentrations. Tick bioassays were conducted by applying 1.0 ml of thetest substance to clean dry glass plates confined by 10 cm grease pencilcircles drawn on the plates and spread evenly with an acid brush. Theplates were allowed to dry for at least 1 hour before adult ticks wereconfined to the treated substrate using 10 cm Petri dish lids. Eachtreatment was replicated 5 times. Approximately 5 adult ticks wereplaced into each replicate. Mortality was assessed at 2, 8, 24 and 48hours after introduction of the ticks into the test system. The meanpercent mortality for each dosage group and time interval was determinedand results from the 48-hour observation are presented in Table 10.

TABLE 10 Activity against brown dog tick. Comp # Conc., ppm % Tickmortality 2  50 ppm 28 500 ppm 61

Insecticide Utility

The compounds of the invention are useful for the control ofinvertebrates including insects. Therefore, the present invention alsois directed to a method for inhibiting an insect which comprisesapplying an insect-inhibiting amount of a compound of formula (I) to alocus of the insect, to the area to be protected, or directly on theinsect to be controlled. The compounds of the invention may also be usedto control other invertebrate pests such as mites and nematodes.

The “locus” of insects or other pests is a term used herein to refer tothe environment in which the insects or other pests live or where theireggs are present, including the air surrounding them, the food they eat,or objects which they contact. For example, insects which eat, damage orcontact edible, commodity, ornamental, turf or pasture plants can becontrolled by applying the active compounds to the seed of the plantbefore planting, to the seedling, or cutting which is planted, theleaves, stems, fruits, grain, and/or roots, or to the soil or othergrowth medium before or after the crop is planted. Protection of theseplants against virus, fungus or bacterium diseases may also be achievedindirectly through controlling sap-feeding pests such as whitefly, planthopper, aphid and spider mite. Such plants include those which are bredthrough conventional approaches and which are genetically modified usingmodern biotechnology to gain insect-resistant, herbicide-resistant,nutrition-enhancement, and/or any other beneficial traits.

It is contemplated that the compounds might also be useful to protecttextiles, paper, stored grain, seeds and other foodstuffs, houses andother buildings which may be occupied by humans and/or companion, farm,ranch, zoo, or other animals, by applying an active compound to or nearsuch objects. Domesticated animals, buildings or human beings might beprotected with the compounds by controlling invertebrate and/or nematodepests that are parasitic or are capable of transmitting infectiousdiseases. Such pests include, for example, chiggers, ticks, lice,mosquitoes, flies, fleas and heartworms. Nonagronomic applications alsoinclude invertebrate pest control in forests, in yards, along road sidesand railroad right of way.

The term “inhibiting an insect” refers to a decrease in the numbers ofliving insects, or a decrease in the number of viable insect eggs. Theextent of reduction accomplished by a compound depends, of course, uponthe application rate of the compound, the particular compound used, andthe target insect species. At least an inactivating amount should beused. The term “insect-inactivating amount” is used to describe theamount, which is sufficient to cause a measurable reduction in thetreated insect population. Generally an amount in the range from about 1to about 1000 ppm by weight active compound is used. For example,insects or other pests which can be inhibited include, but are notlimited to:

Lepidoptera—Heliothis spp., Helicoverpa spp., Spodoptera spp., Mythimnaunipuncta, Agrotis ipsilon, Earias spp., Euxoa auxiliaris, Trichoplusiani, Anticarsia gemmatalis, Rachiplusia nu, Plutella xylostella, Chilospp., Scirpophaga incertulas, Sesamia inferens, Cnaphalocrocismedinalis, Ostrinia nubilalis, Cydia pomonella, Carposina niponensis,Adoxophyes orana, Archips argyrospilus, Pandemis heparana, Epinotiaaporema, Eupoecilia ambiguella, Lobesia botrana, Polychrosis viteana,Pectinophora gossypiella, Pieris rapae, Phyllonorycter spp., Leucopteramalifoliella, Phyllocnisitis citrellaColeoptera—Diabrotica spp., Leptinotarsa decemlineata, Oulema oryzae,Anthonomus grandis, Lissorhoptrus oryzophilus, Agriotes spp., Melanotuscommunis, Popillia japonica, Cyclocephala spp., Tribolium spp.Homoptera—Aphis spp., Myzus persicae, Rhopalosiphum spp., Dysaphisplantaginea, Toxoptera spp., Macrosiphum euphorbiae, Aulacorthum solani,Sitobion avenae, Metopolophium dirhodum, Schizaphis graminum,Brachycolus noxius, Nephotettix spp., Nilaparvata lugens, Sogatellafurcifera, Laodelphax striatellus, Bemisia tabaci, Trialeurodesvaporariorum, Aleurodes proletella, Aleurothrixus floccosus,Quadraspidiotus perniciosus, Unaspis yanonensis, Ceroplastes rubens,Aonidiella aurantiiHemiptera—Lygus spp., Eurygaster maura, Nezara viridula, Piezodorusguildingi, Leptocorisa varicornis, Cimex lectularius, Cimex hemipterusThysanoptera—Frankliniella spp., Thrips spp., Scirtothrips dorsalisIsoptera—Reticulitermes flavipes, Coptotermes formosanus, Reticulitermesvirginicus, Heterotermes aureus, Reticulitermes hesperus, Coptotermesfrenchii, Shedorhinotermes spp., Reticulitermes santonensis,Reticulitermes grassei, Reticulitermes banyulensis, Reticulitermessperatus, Reticulitermes hageni, Reticulitermes tibialis, Zootermopsisspp., Incisitermes spp., Marginitermes spp., Macrotermes spp.,Microcerotermes spp., Microtermes spp.Diptera—Liriomyza spp., Musca domestica, Aedes spp., Culex spp.,Anopheles spp., Fannia spp., Stomoxys spp.,Hymenoptera—Iridomyrmex humilis, Solenopsis spp., Monomorium pharaonis,Atta spp., Pogonomyrmex spp., Camponotus spp., Monomorium spp., Tapinomasessile, Tetramorium spp., Xylocapa spp., Vespula spp., Polistes spp.Mallophaga (chewing lice)Anoplura (sucking lice)—Pthirus pubis, Pediculus spp.Orthoptera (grasshoppers, crickets)—Melanoplus spp., Locusta migratoria,Schistocerca gregaria, Gryllotalpidae (mole crickets).Blattoidea (cockroaches)—Blatta orientalis, Blattella germanica,Periplaneta americana, Supella longipalpa, Periplaneta australasiae,Periplaneta brunnea, Parcoblatta pennsylvanica, Periplaneta fuliginosa,Pycnoscelus surinamensis,Siphonaptera—Ctenophalides spp., Pulex irritansAcari—Tetranychus spp., Panonychus spp., Eotetranychus carpini,Phyllocoptruta oleivora, Aculus pelekassi, Brevipalpus phoenicis,Boophilus spp., Dermacentor variabilis, Rhipicephalus sanguineus,Amblyomma americanum, Ixodes spp., Notoedres cati, Sarcoptes scabiei,Dermatophagoides spp.Nematoda—Dirofilaria immitis, Meloidogyne spp., Heterodera spp.,Hoplolaimus columbus, Belonolaimus spp., Pratylenchus spp., Rotylenchusreniformis, Criconemella ornata, Ditylenchus spp., Aphelenchoidesbesseyi, Hirschmanniella spp.

Compositions

The compounds of this invention are applied in the form of compositionswhich are important embodiments of the invention, and which comprise acompound of this invention and a phytologically-acceptable inertcarrier. Control of the pests is achieved by applying compounds of theinvention in forms of sprays, topical treatment, gels, seed coatings,microcapsulations, systemic uptake, baits, eartags, boluses, foggers,fumigants aerosols, dusts and many others. The compositions are eitherconcentrated solid or liquid formulations which are dispersed in waterfor application, or are dust or granular formulations which are appliedwithout further treatment. The compositions are prepared according toprocedures and formulae which are conventional in the agriculturalchemical art, but which are novel and important because of the presencetherein of the compounds of this invention. Some description of theformulation of the compositions will be given, however, to assure thatagricultural chemists can readily prepare any desired composition.

The dispersions in which the compounds are applied are most oftenaqueous suspensions or emulsions prepared from concentrated formulationsof the compounds. Such water-soluble, water-suspendable or emulsifiableformulations are either solids, usually known as wettable powders, orliquids usually known as emulsifiable concentrates or aqueoussuspensions. Wettable powders, which may be compacted to form waterdispersible granules, comprise an intimate mixture of the activecompound, an inert carrier, and surfactants. The concentration of theactive compound is usually from about 10% to about 90% by weight. Theinert carrier is usually chosen from among the attapulgite clays, themontmorillonite clays, the diatomaceous earths, or the purifiedsilicates. Effective surfactants, comprising from about 0.5% to about10% of the wettable powder, are found among the sulfonated lignins, thecondensed naphthalenesulfonates, the naphthalenesulfonates, thealkylbenzenesulfonates, the alkyl sulfates, and nonionic surfactantssuch as ethylene oxide adducts of alkyl phenols.

Emulsifiable concentrates of the compounds comprise a convenientconcentration of a compound, such as from about 50 to about 500 gramsper liter of liquid, equivalent to about 10% to about 50%, dissolved inan inert carrier which is either a water miscible solvent or a mixtureof water-immiscible organic solvent and emulsifiers. Useful organicsolvents include aromatics, especially the xylenes, and the petroleumfractions, especially the high-boiling naphthalenic and olefinicportions of petroleum such as heavy aromatic naphtha. Other organicsolvents may also be used, such as the terpenic solvents including rosinderivatives, aliphatic ketones such as cyclohexanone, and complexalcohols such as 2-ethoxyethanol. Suitable emulsifiers for emulsifiableconcentrates are chosen from conventional anionic and/or nonionicsurfactants, such as those discussed above.

Aqueous suspensions comprise suspensions of water-insoluble compounds ofthis invention, dispersed in an aqueous vehicle at a concentration inthe range from about 5% to about 50% by weight. Suspensions are preparedby finely grinding the compound, and vigorously mixing it into a vehiclecomprised of water and surfactants chosen from the same types discussedabove. Inert ingredients, such as inorganic salts and synthetic ornatural gums, may also be added, to increase the density and viscosityof the aqueous vehicle. It is often most effective to grind and mix thecompound at the same time by preparing the aqueous mixture, andhomogenizing it in an implement such as a sand mill, ball mill, orpiston-type homogenizer.

The compounds may also be applied as granular compositions, which areparticularly useful for applications to the soil. Granular compositionsusually contain from about 0.5% to about 10% by weight of the compound,dispersed in an inert carrier which consists entirely or in large partof clay or a similar inexpensive substance. Such compositions areusually prepared by dissolving the compound in a suitable solvent andapplying it to a granular carrier which has been pre-formed to theappropriate particle size, in the range of from about 0.5 to 3 mm Suchcompositions may also be formulated by making a dough or paste of thecarrier and compound and crushing and drying to obtain the desiredgranular particle size.

Dusts containing the compounds are prepared simply by intimately mixingthe compound in powdered form with a suitable dusty agriculturalcarrier, such as kaolin clay, ground volcanic rock, and the like. Dustscan suitably contain from about 1% to about 10% of the compound.

It is equally practical, when desirable for any reason, to apply thecompound in the form of a solution in an appropriate organic solvent,usually a bland petroleum oil, such as the spray oils, which are widelyused in agricultural chemistry.

Insecticides and acaricides are generally applied in the form of adispersion of the active ingredient in a liquid carrier. It isconventional to refer to application rates in terms of the concentrationof active ingredient in the carrier. The most widely used carrier iswater.

The compounds of the invention can also be applied in the form of anaerosol composition. In such compositions the active compound isdissolved or dispersed in an inert carrier, which is apressure-generating propellant mixture.

The aerosol composition is packaged in a container from which themixture is dispensed through an atomizing valve. Propellant mixturescomprise either low-boiling halocarbons, which may be mixed with organicsolvents, or aqueous suspensions pressurized with inert gases or gaseoushydrocarbons.

The actual amount of compound to be applied to loci of insects and mitesis not critical and can readily be determined by those skilled in theart in view of the examples above. In general, concentrations from 10ppm to 5000 ppm by weight of compound are expected to provide goodcontrol. With many of the compounds, concentrations from 100 to 1500 ppmwill suffice.

The locus to which a compound is applied can be any locus inhabited byan insect or mite, for example, vegetable crops, fruit and nut trees,grape vines, ornamental plants, domesticated animals, the interior orexterior surfaces of buildings, and the soil around buildings.

Because of the unique ability of insect eggs to resist toxicant action,repeated applications may be desirable to control newly emerged larvae,as is true of other known insecticides and acaricides.

Systemic movement of compounds of the invention in plants may beutilized to control pests on one portion of the plant by applying thecompounds to a different portion of it. For example, control offoliar-feeding insects can be controlled by drip irrigation or furrowapplication, or by treating the seed before planting. Seed treatment canbe applied to all types of seeds, including those from which plantsgenetically transformed to express specialized traits will germinate.Representative examples include those expressing proteins toxic toinvertebrate pests, such as Bacillus thuringiensis or other insecticidalproteins, those expressing herbicide resistance, such as “RoundupReady®” seed, or those with “stacked” foreign genes expressinginsecticidal proteins, herbicide resistance, nutrition-enhancementand/or any other beneficial traits.

An insecticidal bait composition consisting of compounds of the presentinvention and attractants and/or feeding stimulants may be used toincrease efficacy of the insecticides against insect pest in a devicesuch as trap, bait station, and the like. The bait composition isusually a solid, semi-solid (including gel) or liquid bait matrixincluding the stimulants and one or more non-microencapsulated ormicroencapsulated insecticides in an amount effective to act as killagents.

The compounds of the present invention (Formula I) are often applied inconjunction with one or more other insecticides or fungicides orherbicides to obtain control of a wider variety of pests diseases andweeds. When used in conjunction with other insecticides or fungicides orherbicides, the presently claimed compounds can be formulated with theother insecticides or fungicides or herbicide, tank mixed with the otherinsecticides or fungicides or herbicides, or applied sequentially withthe other insecticides or fungicides or herbicides.

Some of the insecticides that can be employed beneficially incombination with the compounds of the present invention include:antibiotic insecticides such as allosamidin and thuringiensin;macrocyclic lactone insecticides such as spinosad, spinetoram, and otherspinosyns including the 21-butenyl spinosyns and their derivatives;avermectin insecticides such as abamectin, doramectin, emamectin,eprinomectin, ivermectin and selamectin; milbemycin insecticides such aslepimectin, milbemectin, milbemycin oxime and moxidectin; arsenicalinsecticides such as calcium arsenate, copper acetoarsenite, copperarsenate, lead arsenate, potassium arsenite and sodium arsenite;biological insecticides such as Bacillus popilliae, B. sphaericus, B.thuringiensis subsp. aizawai, B. thuringiensis subsp. kurstaki, B.thuringiensis subsp. tenebrionis, Beauveria bassiana, Cydia pomonellagranulosis virus, Douglas fir tussock moth NPV, gypsy moth NPV,Helicoverpa zea NPV, Indian meal moth granulosis virus, Metarhiziumanisopliae, Nosema locustae, Paecilomyces fumosoroseus, P. lilacinus,Photorhabdus luminescens, Spodoptera exigua NPV, trypsin modulatingoostatic factor, Xenorhabdus nematophilus, and X. bovienii, plantincorporated protectant insecticides such as Cry1Ab, Cry1Ac, Cry1F,Cry1A.105, Cry2Ab2, Cry3A, mir Cry3A, Cry3Bbl, Cry34, Cry35, and VIP3A;botanical insecticides such as anabasine, azadirachtin, d-limonene,nicotine, pyrethrins, cinerins, cinerin I, cinerin II, jasmolin I,jasmolin II, pyrethrin I, pyrethrin II, quassia, rotenone, ryania andsabadilla; carbamate insecticides such as bendiocarb and carbaryl;benzofuranyl methylcarbamate insecticides such as benfuracarb,carbofuran, carbosulfan, decarbofuran and furathiocarb;dimethylcarbamate insecticides dimitan, dimetilan, hyquincarb andpirimicarb; oxime carbamate insecticides such as alanycarb, aldicarb,aldoxycarb, butocarboxim, butoxycarboxim, methomyl, nitrilacarb, oxamyl,tazimcarb, thiocarboxime, thiodicarb and thiofanox; phenylmethylcarbamate insecticides such as allyxycarb, aminocarb, bufencarb,butacarb, carbanolate, cloethocarb, dicresyl, dioxacarb, EMPC,ethiofencarb, fenethacarb, fenobucarb, isoprocarb, methiocarb,metolcarb, mexacarbate, promacyl, promecarb, propoxur, trimethacarb, XMCand xylylcarb; dinitrophenol insecticides such as dinex, dinoprop,dinosam and DNOC; fluorine insecticides such as bariumhexafluorosilicate, cryolite, sodium fluoride, sodium hexafluorosilicateand sulfluramid; formamidine insecticides such as amitraz,chlordimeform, formetanate and formparanate; fumigant insecticides suchas acrylonitrile, carbon disulfide, carbon tetrachloride, chloroform,chloropicrin, para-dichlorobenzene, 1,2-dichloropropane, ethyl formate,ethylene dibromide, ethylene dichloride, ethylene oxide, hydrogencyanide, iodomethane, methyl bromide, methylchloroform, methylenechloride, naphthalene, phosphine, sulfuryl fluoride andtetrachloroethane; inorganic insecticides such as borax, calciumpolysulfide, copper oleate, mercurous chloride, potassium thiocyanateand sodium thiocyanate; chitin synthesis inhibitors such asbistrifluron, buprofezin, chlorfluazuron, cyromazine, diflubenzuron,flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron,noviflumuron, penfluron, teflubenzuron and triflumuron; juvenile hormonemimics such as epofenonane, fenoxycarb, hydroprene, kinoprene,methoprene, pyriproxyfen and triprene; juvenile hormones such asjuvenile hormone I, juvenile hormone II and juvenile hormone III;moulting hormone agonists such as chromafenozide, halofenozide,methoxyfenozide and tebufenozide; moulting hormones such as α-ecdysoneand ecdysterone; moulting inhibitors such as diofenolan; precocenes suchas precocene I, precocene II and precocene III; unclassified insectgrowth regulators such as dicyclanil; nereistoxin analogue insecticidessuch as bensultap, cartap, thiocyclam and thiosultap; nicotinoidinsecticides such as flonicamid; nitroguanidine insecticides such asclothianidin, dinotefuran, imidacloprid and thiamethoxam; nitromethyleneinsecticides such as nitenpyram and nithiazine; pyridylmethylamineinsecticides such as acetamiprid, imidacloprid, nitenpyram andthiacloprid; organochlorine insecticides such as bromo-DDT, camphechlor,DDT, pp′-DDT, ethyl-DDD, HCH, gamma-HCH, lindane, methoxychlor,pentachlorophenol and TDE; cyclodiene insecticides such as aldrin,bromocyclen, chlorbicyclen, chlordane, chlordecone, dieldrin, dilor,endosulfan, endrin, HEOD, heptachlor, HHDN, isobenzan, isodrin, kelevanand mirex; organophosphate insecticides such as bromfenvinfos,chlorfenvinphos, crotoxyphos, dichlorvos, dicrotophos, dimethylvinphos,fospirate, heptenophos, methocrotophos, mevinphos, monocrotophos, naled,naftalofos, phosphamidon, propaphos, TEPP and tetrachlorvinphos;organothiophosphate insecticides such as dioxabenzofos, fosmethilan andphenthoate; aliphatic organothiophosphate insecticides such as acethion,amiton, cadusafos, chlorethoxyfos, chlormephos, demephion, demephion-O,demephion-S, demeton, demeton-O, demeton-S, demeton-methyl,demeton-O-methyl, demeton-S-methyl, demeton-S-methylsulphon, disulfoton,ethion, ethoprophos, IPSP, isothioate, malathion, methacrifos,oxydemeton-methyl, oxydeprofos, oxydisulfoton, phorate, sulfotep,terbufos and thiometon; aliphatic amide organothiophosphate insecticidessuch as amidithion, cyanthoate, dimethoate, ethoate-methyl, formothion,mecarbam, omethoate, prothoate, sophamide and vamidothion; oximeorganothiophosphate insecticides such as chlorphoxim, phoxim andphoxim-methyl; heterocyclic organothiophosphate insecticides such asazamethiphos, coumaphos, coumithoate, dioxathion, endothion, menazon,morphothion, phosalone, pyraclofos, pyridaphenthion and quinothion;benzothiopyran organothiophosphate insecticides such as dithicrofos andthicrofos; benzotriazine organothiophosphate insecticides such asazinphos-ethyl and azinphos-methyl; isoindole organothiophosphateinsecticides such as dialifos and phosmet; isoxazole organothiophosphateinsecticides such as isoxathion and zolaprofos; pyrazolopyrimidineorganothiophosphate insecticides such as chlorprazophos and pyrazophos;pyridine organothiophosphate insecticides such as chlorpyrifos andchlorpyrifos-methyl; pyrimidine organothiophosphate insecticides such asbutathiofos, diazinon, etrimfos, lirimfos, pirimiphos-ethyl,pirimiphos-methyl, primidophos, pyrimitate and tebupirimfos; quinoxalineorganothiophosphate insecticides such as quinalphos andquinalphos-methyl; thiadiazole organothiophosphate insecticides such asathidathion, lythidathion, methidathion and prothidathion; triazoleorganothiophosphate insecticides such as isazofos and triazophos; phenylorganothiophosphate insecticides such as azothoate, bromophos,bromophos-ethyl, carbophenothion, chlorthiophos, cyanophos, cythioate,dicapthon, dichlofenthion, etaphos, famphur, fenchlorphos, fenitrothionfensulfothion, fenthion, fenthion-ethyl, heterophos, jodfenphos,mesulfenfos, parathion, parathion-methyl, phenkapton, phosnichlor,profenofos, prothiofos, sulprofos, temephos, trichlormetaphos-3 andtrifenofos; phosphonate insecticides such as butonate and trichlorfon;phosphonothioate insecticides such as mecarphon; phenylethylphosphonothioate insecticides such as fonofos and trichloronat;phenyl phenylphosphonothioate insecticides such as cyanofenphos, EPN andleptophos; phosphoramidate insecticides such as crufomate, fenamiphos,fosthietan, mephosfolan, phosfolan and pirimetaphos;phosphoramidothioate insecticides such as acephate, isocarbophos,isofenphos, methamidophos and propetamphos; phosphorodiamideinsecticides such as dimefox, mazidox, mipafox and schradan; oxadiazineinsecticides such as indoxacarb; phthalimide insecticides such asdialifos, phosmet and tetramethrin; pyrazole insecticides such asacetoprole, ethiprole, fipronil, pyrafluprole, pyriprole, tebufenpyrad,tolfenpyrad and vaniliprole; pyrethroid ester insecticides such asacrinathrin, allethrin, bioallethrin, barthrin, bifenthrin,bioethanomethrin, cyclethrin, cycloprothrin, cyfluthrin,beta-cyfluthrin, cyhalothrin, gamma-cyhalothrin, lambda-cyhalothrin,cypermethrin, alpha-cypermethrin, beta-cypermethrin, theta-cypermethrin,zeta-cypermethrin, cyphenothrin, deltamethrin, dimefluthrin, dimethrin,empenthrin, fenfluthrin, fenpirithrin, fenpropathrin, fenvalerate,esfenvalerate, flucythrinate, fluvalinate, tau-fluvalinate, furethrin,imiprothrin, metofluthrin, permethrin, biopermethrin, transpermethrin,phenothrin, prallethrin, profluthrin, pyresmethrin, resmethrin,bioresmethrin, cismethrin, tefluthrin, terallethrin, tetramethrin,tralomethrin and transfluthrin; pyrethroid ether insecticides such asetofenprox, flufenprox, halfenprox, protrifenbute and silafluofen;pyrimidinamine insecticides such as flufenerim and pyrimidifen; pyrroleinsecticides such as chlorfenapyr; tetronic acid insecticides such asspirodiclofen, spiromesifen and spirotetramat; thiourea insecticidessuch as diafenthiuron; urea insecticides such as flucofuron andsulcofuron; and unclassified insecticides such as AKD-3088, closantel,crotamiton, cyflumetofen, E2Y45, EXD, fenazaflor, fenazaquin,fenoxacrim, fenpyroximate, FKI-1033, flubendiamide, HGW86,hydramethylnon, IKI-2002, isoprothiolane, malonoben, metaflumizone,metoxadiazone, nifluridide, NNI-9850, NNI-0101, pymetrozine, pyridaben,pyridalyl, Qcide, rafoxanide, rynaxypyr, SYJ-159, triarathene andtriazamate and any combinations thereof

Some of the fungicides that can be employed beneficially in combinationwith the compounds of the present invention include:2-(thiocyanatomethylthio)-benzothiazole, 2-phenylphenol,8-hydroxyquinoline sulfate, Ampelomyces, quisqualis, azaconazole,azoxystrobin, Bacillus subtilis, benalaxyl, benomyl,benthiavalicarb-isopropyl, benzylaminobenzene-sulfonate (BABS) salt,bicarbonates, biphenyl, bismerthiazol, bitertanol, blasticidin-S, borax,Bordeaux mixture, boscalid, bromuconazole, bupirimate, calciumpolysulfide, captafol, captan, carbendazim, carboxin, carpropamid,carvone, chloroneb, chlorothalonil, chlozolinate, Coniothyrium minitans,copper hydroxide, copper octanoate, copper oxychloride, copper sulfate,copper sulfate (tribasic), cuprous oxide, cyazofamid, cyflufenamid,cymoxanil, cyproconazole, cyprodinil, dazomet, debacarb, diammoniumethylenebis-(dithiocarbamate), dichlofluanid, dichlorophen, diclocymet,diclomezine, dichloran, diethofencarb, difenoconazole, difenzoquat ion,diflumetorim, dimethomorph, dimoxystrobin, diniconazole, diniconazole-M,dinobuton, dinocap, diphenylamine, dithianon, dodemorph, dodemorphacetate, dodine, dodine free base, edifenphos, epoxiconazole, ethaboxam,ethoxyquin, etridiazole, famoxadone, fenamidone, fenarimol,fenbuconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil,fenpropidin, fenpropimorph, fentin, fentin acetate, fentin hydroxide,ferbam, ferimzone, fluazinam, fludioxonil, flumorph, fluopicolide,fluoroimide, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide,flutolanil, flutriafol, folpet, formaldehyde, fosetyl,fosetyl-aluminium, fuberidazole, furalaxyl, furametpyr, guazatine,guazatine acetates, GY-81, hexachlorobenzene, hexaconazole, hymexazol,imazalil, imazalil sulfate, imibenconazole, iminoctadine, iminoctadinetriacetate, iminoctadine tris(albesilate), ipconazole, iprobenfos,iprodione, iprovalicarb, isoprothiolane, kasugamycin, kasugamycinhydrochloride hydrate, kresoxim-methyl, mancopper, mancozeb, maneb,mepanipyrim, mepronil, mercuric chloride, mercuric oxide, mercurouschloride, metalaxyl, mefenoxam, metalaxyl-M, metam, metam-ammonium,metam-potassium, metam-sodium, metconazole, methasulfocarb, methyliodide, methyl isothiocyanate, metiram, metominostrobin, metrafenone,mildiomycin, myclobutanil, nabam, nitrothal-isopropyl, nuarimol,octhilinone, ofurace, oleic acid (fatty acids), orysastrobin, oxadixyl,oxine-copper, oxpoconazole fumarate, oxycarboxin, pefurazoate,penconazole, pencycuron, pentachlorophenol, pentachlorophenyl laurate,penthiopyrad, phenylmercury acetate, phosphonic acid, phthalide,picoxystrobin, polyoxin B, polyoxins, polyoxorim, potassium bicarbonate,potassium hydroxyquinoline sulfate, probenazole, prochloraz,procymidone, propamocarb, propamocarb hydrochloride, propiconazole,propineb, proquinazid, prothioconazole, pyraclostrobin, pyrazophos,pyributicarb, pyrifenox, pyrimethanil, pyroquilon, quinoclamine,quinoxyfen, quintozene, Reynoutria sachalinensis extract, silthiofam,simeconazole, sodium 2-phenylphenoxide, sodium bicarbonate, sodiumpentachlorophenoxide, spiroxamine, sulfur, SYP-Z071, tar oils,tebuconazole, tecnazene, tetraconazole, thiabendazole, thifluzamide,thiophanate-methyl, thiram, tiadinil, tolclofos-methyl, tolylfluanid,triadimefon, triadimenol, triazoxide, tricyclazole, tridemorph,trifloxystrobin, triflumizole, triforine, triticonazole, validamycin,vinclozolin, zineb, ziram, zoxamide, Candida oleophila, Fusariumoxysporum, Gliocladium spp., Phlebiopsis gigantean, Streptomycesgriseoviridis, Trichoderma spp.,(RS)—N-(3,5-dichlorophenyl)-2-(methoxymethyl)-succinimide,1,2-dichloropropane, 1,3-dichloro-1,1,3,3-tetrafluoroacetone hydrate,1-chloro-2,4-dinitronaphthalene, 1-chloro-2-nitropropane,2-(2-heptadecyl-2-imidazolin-1-yl)ethanol,2,3-dihydro-5-phenyl-1,4-dithi-ine 1,1,4,4-tetraoxide,2-methoxyethylmercury acetate, 2-methoxyethylmercury chloride,2-methoxyethylmercury silicate, 3-(4-chlorophenyl)-5-methylrhodanine,4-(2-nitroprop-1-enyl)phenyl thiocyanateme: ampropylfos, anilazine,azithiram, barium polysulfide, Bayer 32394, benodanil, benquinox,bentaluron, benzamacril; benzamacril-isobutyl, benzamorf, binapacryl,bis(methylmercury) sulfate, bis(tributyltin) oxide, buthiobate, cadmiumcalcium copper zinc chromate sulfate, carbamorph, CECA, chlobenthiazone,chloraniformethan, chlorfenazole, chlorquinox, climbazole, copperbis(3-phenylsalicylate), copper zinc chromate, cufraneb, cuprichydrazinium sulfate, cuprobam, cyclafuramid, cypendazole, cyprofuram,decafentin, dichlone, dichlozoline, diclobutrazol, dimethirimol,dinocton, dinosulfon, dinoterbon, dipyrithione, ditalimfos, dodicin,drazoxolon, EBP, ESBP, etaconazole, etem, ethirim, fenaminosulf,fenapanil, fenitropan, fluotrimazole, furcarbanil, furconazole,furconazole-cis, furmecyclox, furophanate, glyodine, griseofulvin,halacrinate, Hercules 3944, hexylthiofos, ICIA0858, isopamphos,isovaledione, mebenil, mecarbinzid, metazoxolon, methfuroxam,methylmercury dicyandiamide, metsulfovax, milneb, mucochloric anhydride,myclozolin, N-3,5-dichlorophenyl-succinimide,N-3-nitrophenylitaconimide, natamycin,N-ethylmercurio-4-toluenesulfonanilide, nickelbis(dimethyldithiocarbamate), OCH, phenylmercurydimethyldithiocarbamate, phenylmercury nitrate, phosdiphen, prothiocarb;prothiocarb hydrochloride, pyracarbolid, pyridinitril, pyroxychlor,pyroxyfur, quinacetol; quinacetol sulfate, quinazamid, quinconazole,rabenzazole, salicylanilide, SSF-109, sultropen, tecoram, thiadifluor,thicyofen, thiochlorfenphim, thiophanate, thioquinox, tioxymid,triamiphos, triarimol, triazbutil, trichlamide, urbacid, XRD-563, andzarilamid, and any combinations thereof.

Some of the herbicides that can be employed in conjunction with thecompounds of the present invention include: amide herbicides such asallidochlor, beflubutamid, benzadox, benzipram, bromobutide,cafenstrole, CDEA, chlorthiamid, cyprazole, dimethenamid,dimethenamid-P, diphenamid, epronaz, etnipromid, fentrazamide, flupoxam,fomesafen, halosafen, isocarbamid, isoxaben, napropamide, naptalam,pethoxamid, propyzamide, quinonamid and tebutam; anilide herbicides suchas chloranocryl, cisanilide, clomeprop, cypromid, diflufenican,etobenzanid, fenasulam, flufenacet, flufenican, mefenacet, mefluidide,metamifop, monalide, naproanilide, pentanochlor, picolinafen andpropanil; arylalanine herbicides such as benzoylprop, flamprop andflamprop-M; chloroacetanilide herbicides such as acetochlor, alachlor,butachlor, butenachlor, delachlor, diethatyl, dimethachlor, metazachlor,metolachlor, S-metolachlor, pretilachlor, propachlor, propisochlor,prynachlor, terbuchlor, thenylchlor and xylachlor; sulfonanilideherbicides such as benzofluor, perfluidone, pyrimisulfan and profluazol;sulfonamide herbicides such as asulam, carbasulam, fenasulam andoryzalin; antibiotic herbicides such as bilanafos; benzoic acidherbicides such as chloramben, dicamba, 2,3,6-TBA and tricamba;pyrimidinyloxybenzoic acid herbicides such as bispyribac andpyriminobac; pyrimidinylthiobenzoic acid herbicides such as pyrithiobac;phthalic acid herbicides such as chlorthal; picolinic acid herbicidessuch as aminopyralid, clopyralid and picloram; quinolinecarboxylic acidherbicides such as quinclorac and quinmerac; arsenical herbicides suchas cacodylic acid, CMA, DSMA, hexaflurate, MAA, MAMA, MSMA, potassiumarsenite and sodium arsenite; benzoylcyclohexanedione herbicides such asmesotrione, sulcotrione, tefuryltrione and tembotrione; benzofuranylalkylsulfonate herbicides such as benfuresate and ethofumesate;carbamate herbicides such as asulam, carboxazole chlorprocarb,dichlormate, fenasulam, karbutilate and terbucarb; carbanilateherbicides such as barban, BCPC, carbasulam, carbetamide, CEPC,chlorbufam, chlorpropham, CPPC, desmedipham, phenisopham, phenmedipham,phenmedipham-ethyl, propham and swep; cyclohexene oxime herbicides suchas alloxydim, butroxydim, clethodim, cloproxydim, cycloxydim,profoxydim, sethoxydim, tepraloxydim and tralkoxydim;cyclopropylisoxazole herbicides such as isoxachlortole and isoxaflutole;dicarboximide herbicides such as benzfendizone, cinidon-ethyl, flumezin,flumiclorac, flumioxazin and flumipropyn; dinitroaniline herbicides suchas benfluralin, butralin, dinitramine, ethalfluralin, fluchloralin,isopropalin, methalpropalin, nitralin, oryzalin, pendimethalin,prodiamine, profluralin and trifluralin; dinitrophenol herbicides suchas dinofenate, dinoprop, dinosam, dinoseb, dinoterb, DNOC, etinofen andmedinoterb; diphenyl ether herbicides such as ethoxyfen; nitrophenylether herbicides such as acifluorfen, aclonifen, bifenox,chlomethoxyfen, chlornitrofen, etnipromid, fluorodifen, fluoroglycofen,fluoronitrofen, fomesafen, furyloxyfen, halosafen, lactofen, nitrofen,nitrofluorfen and oxyfluorfen; dithiocarbamate herbicides such asdazomet and metam; halogenated aliphatic herbicides such as alorac,chloropon, dalapon, flupropanate, hexachloroacetone, iodomethane, methylbromide, monochloroacetic acid, SMA and TCA; imidazolinone herbicidessuch as imazamethabenz, imazamox, imazapic, imazapyr, imazaquin andimazethapyr; inorganic herbicides such as ammonium sulfamate, borax,calcium chlorate, copper sulfate, ferrous sulfate, potassium azide,potassium cyanate, sodium azide, sodium chlorate and sulfuric acid;nitrile herbicides such as bromobonil, bromoxynil, chloroxynil,dichlobenil, iodobonil, ioxynil and pyraclonil; organophosphorusherbicides such as amiprofos-methyl, anilofos, bensulide, bilanafos,butamifos, 2,4-DEP, DMPA, EBEP, fosamine, glufosinate, glyphosate andpiperophos; phenoxy herbicides such as bromofenoxim, clomeprop, 2,4-DEB,2,4-DEP, difenopenten, disul, erbon, etnipromid, fenteracol andtrifopsime; phenoxyacetic herbicides such as 4-CPA, 2,4-D, 3,4-DA, MCPA,MCPA-thioethyl and 2,4,5-T; phenoxybutyric herbicides such as 4-CPB,2,4-DB, 3,4-DB, MCPB and 2,4,5-TB; phenoxypropionic herbicides such ascloprop, 4-CPP, dichlorprop, dichlorprop-P, 3,4-DP, fenoprop, mecopropand mecoprop-P; aryloxyphenoxypropionic herbicides such as chlorazifop,clodinafop, clofop, cyhalofop, diclofop, fenoxaprop, fenoxaprop-P,fenthiaprop, fluazifop, fluazifop-P, haloxyfop, haloxyfop-P,isoxapyrifop, metamifop, propaquizafop, quizalofop, quizalofop-P andtrifop; phenylenediamine herbicides such as dinitramine and prodiamine;pyrazolyl herbicides such as benzofenap, pyrazolynate, pyrasulfotole,pyrazoxyfen, pyroxasulfone and topramezone; pyrazolylphenyl herbicidessuch as fluazolate and pyraflufen; pyridazine herbicides such ascredazine, pyridafol and pyridate; pyridazinone herbicides such asbrompyrazon, chloridazon, dimidazon, flufenpyr, metflurazon,norflurazon, oxapyrazon and pydanon; pyridine herbicides such asaminopyralid, cliodinate, clopyralid, dithiopyr, fluroxypyr, haloxydine,picloram, picolinafen, pyriclor, thiazopyr and triclopyr;pyrimidinediamine herbicides such as iprymidam and tioclorim; quaternaryammonium herbicides such as cyperquat, diethamquat, difenzoquat, diquat,morfamquat and paraquat; thiocarbamate herbicides such as butylate,cycloate, di-allate, EPTC, esprocarb, ethiolate, isopolinate,methiobencarb, molinate, orbencarb, pebulate, prosulfocarb,pyributicarb, sulfallate, thiobencarb, tiocarbazil, tri-allate andvernolate; thiocarbonate herbicides such as dimexano, EXD and proxan;thiourea herbicides such as methiuron; triazine herbicides such asdipropetryn, triaziflam and trihydroxytriazine; chlorotriazineherbicides such as atrazine, chlorazine, cyanazine, cyprazine,eglinazine, ipazine, mesoprazine, procyazine, proglinazine, propazine,sebuthylazine, simazine, terbuthylazine and trietazine; methoxytriazineherbicides such as atraton, methometon, prometon, secbumeton, simetonand terbumeton; methylthiotriazine herbicides such as ametryn,aziprotryne, cyanatryn, desmetryn, dimethametryn, methoprotryne,prometryn, simetryn and terbutryn; triazinone herbicides such asametridione, amibuzin, hexazinone, isomethiozin, metamitron andmetribuzin; triazole herbicides such as amitrole, cafenstrole, epronazand flupoxam; triazolone herbicides such as amicarbazone, bencarbazone,carfentrazone, flucarbazone, propoxycarbazone, sulfentrazone andthiencarbazone-methyl; triazolopyrimidine herbicides such ascloransulam, diclosulam, florasulam, flumetsulam, metosulam, penoxsulamand pyroxsulam; uracil herbicides such as butafenacil, bromacil,flupropacil, isocil, lenacil and terbacil; 3-phenyluracils; ureaherbicides such as benzthiazuron, cumyluron, cycluron, dichloralurea,diflufenzopyr, isonoruron, isouron, methabenzthiazuron, monisouron andnoruron; phenylurea herbicides such as anisuron, buturon, chlorbromuron,chloreturon, chlorotoluron, chloroxuron, daimuron, difenoxuron,dimefuron, diuron, fenuron, fluometuron, fluothiuron, isoproturon,linuron, methiuron, methyldymron, metobenzuron, metobromuron, metoxuron,monolinuron, monuron, neburon, parafluron, phenobenzuron, siduron,tetrafluron and thidiazuron; pyrimidinylsulfonylurea herbicides such asamidosulfuron, azimsulfuron, bensulfuron, chlorimuron, cyclosulfamuron,ethoxysulfuron, flazasulfuron, flucetosulfuron, flupyrsulfuron,foramsulfuron, halosulfuron, imazosulfuron, mesosulfuron, nicosulfuron,orthosulfamuron, oxasulfuron, primisulfuron, pyrazosulfuron,rimsulfuron, sulfometuron, sulfosulfuron and trifloxysulfuron;triazinylsulfonylurea herbicides such as chlorsulfuron, cinosulfuron,ethametsulfuron, iodosulfuron, metsulfuron, prosulfuron, thifensulfuron,triasulfuron, tribenuron, triflusulfuron and tritosulfuron;thiadiazolylurea herbicides such as buthiuron, ethidimuron, tebuthiuron,thiazafluron and thidiazuron; and unclassified herbicides such asacrolein, allyl alcohol, azafenidin, benazolin, bentazone,benzobicyclon, buthidazole, calcium cyanamide, cambendichlor,chlorfenac, chlorfenprop, chlorflurazole, chlorflurenol, cinmethylin,clomazone, CPMF, cresol, ortho-dichlorobenzene, dimepiperate, endothal,fluoromidine, fluridone, flurochloridone, flurtamone, fluthiacet,indanofan, methazole, methyl isothiocyanate, nipyraclofen, OCH,oxadiargyl, oxadiazon, oxaziclomefone, pentachlorophenol, pentoxazone,phenylmercury acetate, pinoxaden, prosulfalin, pyribenzoxim, pyriftalid,quinoclamine, rhodethanil, sulglycapin, thidiazimin, tridiphane,trimeturon, tripropindan and tritac.

Before an insecticide can be used or sold commercially, such compoundundergoes lengthy evaluation processes by various governmentalauthorities (local, regional, state, national, international).Voluminous data requirements are specified by regulatory authorities andmust be addressed through data generation and submission by the productregistrant or by another on the product registrant's behalf. Thesegovernmental authorities then review such data and if a determination ofsafety is concluded, provide the potential user and/or seller withproduct registration approval. Thereafter, in that locality where theproduct registration is granted and supported, such user and/or sellermay use and/or sell such compound.

We claim:
 1. A method of controlling insects which comprises applying toa locus where control is desired an insect-inactivating amount of acompound of formula (I)

wherein X represents NO₂ or CN; L represents a single bond; R¹represents (C₁-C₄) alkyl; R² and R³ independently represent hydrogen,(C₁-C₄) alkyl, fluoro, chloro or bromo; n is an integer from 0-3; and Yrepresents (C₁-C₄) haloalkyl.
 2. A method according to claim 1 whereinsaid Y represents —CF₃.
 3. A method according to claim 1 wherein R² andR³ independently represent hydrogen, methyl or ethyl.
 4. A methodaccording to claim 1 wherein said compound has the formula

wherein R² and R³ independently represent hydrogen, methyl, ethyl,fluoro, chloro or bromo; and n is an integer from 1-3.
 5. A methodaccording to claim 1 wherein Y represents CF₃, R¹ represents methyl orethyl, R² and R³ independently represent hydrogen, methyl or ethyl, andn is an integer from 1-3.
 6. A method according to any one of claims 1-5wherein at least one or more other insecticides, one or more herbicides,or one or more fungicides are applied.
 7. A method comprising applying acompound of formula (I)

wherein X represents NO₂ or CN; L represents a single bond; R¹represents (C₁-C₄) alkyl; R² and R³ independently represent hydrogen,(C₁-C₄) alkyl, fluoro, chloro or bromo; n is an integer from 0-3; and Yrepresents (C₁-C₄) haloalkyl to a seed.
 8. A method of controllinginvertebrate or nematode pests that are parasitic or capable oftransmitting infectious diseases which comprises applying to a locuswhere control is desired an invertebrate or nematode-inactivating amountof a compound of formula (I)

wherein X represents NO₂ or CN; L represents a single bond; R¹represents (C₁-C₄) alkyl; R² and R³ independently represent hydrogen,(C₁-C₄) alkyl, fluoro, chloro or bromo; n is an integer from 0-3; and Yrepresents (C₁-C₄) haloalkyl.